TWI587871B - 新穎之聚醣共軛物及其用途 - Google Patents
新穎之聚醣共軛物及其用途 Download PDFInfo
- Publication number
- TWI587871B TWI587871B TW104127282A TW104127282A TWI587871B TW I587871 B TWI587871 B TW I587871B TW 104127282 A TW104127282 A TW 104127282A TW 104127282 A TW104127282 A TW 104127282A TW I587871 B TWI587871 B TW I587871B
- Authority
- TW
- Taiwan
- Prior art keywords
- cancer
- group
- galactopyranosyl
- immunological composition
- optionally substituted
- Prior art date
Links
- 150000004676 glycans Chemical class 0.000 title claims description 71
- -1 C17 Chemical compound 0.000 claims description 138
- 239000000203 mixture Substances 0.000 claims description 85
- 230000001900 immune effect Effects 0.000 claims description 60
- 206010028980 Neoplasm Diseases 0.000 claims description 52
- 238000000034 method Methods 0.000 claims description 52
- 201000011510 cancer Diseases 0.000 claims description 43
- 125000004432 carbon atom Chemical group C* 0.000 claims description 42
- 150000001875 compounds Chemical class 0.000 claims description 39
- 210000004027 cell Anatomy 0.000 claims description 34
- 238000006243 chemical reaction Methods 0.000 claims description 30
- 108091007433 antigens Proteins 0.000 claims description 28
- 102000036639 antigens Human genes 0.000 claims description 28
- 239000000427 antigen Substances 0.000 claims description 27
- 230000028993 immune response Effects 0.000 claims description 24
- 239000000126 substance Substances 0.000 claims description 23
- 229960003983 diphtheria toxoid Drugs 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 19
- 239000002671 adjuvant Substances 0.000 claims description 18
- 229940022399 cancer vaccine Drugs 0.000 claims description 18
- 238000009566 cancer vaccine Methods 0.000 claims description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- 125000003107 substituted aryl group Chemical group 0.000 claims description 18
- 108090000623 proteins and genes Proteins 0.000 claims description 16
- 102000004169 proteins and genes Human genes 0.000 claims description 15
- 239000012634 fragment Substances 0.000 claims description 14
- 206010006187 Breast cancer Diseases 0.000 claims description 13
- 229960000814 tetanus toxoid Drugs 0.000 claims description 12
- 208000026310 Breast neoplasm Diseases 0.000 claims description 11
- 108010071134 CRM197 (non-toxic variant of diphtheria toxin) Proteins 0.000 claims description 10
- 108091003079 Bovine Serum Albumin Proteins 0.000 claims description 9
- 102000014914 Carrier Proteins Human genes 0.000 claims description 9
- 108010078791 Carrier Proteins Proteins 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 230000001588 bifunctional effect Effects 0.000 claims description 8
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 8
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 7
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 7
- 206010033128 Ovarian cancer Diseases 0.000 claims description 7
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 7
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 7
- 206010060862 Prostate cancer Diseases 0.000 claims description 7
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 7
- 229940098773 bovine serum albumin Drugs 0.000 claims description 7
- 201000005202 lung cancer Diseases 0.000 claims description 7
- 208000020816 lung neoplasm Diseases 0.000 claims description 7
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 7
- 201000002528 pancreatic cancer Diseases 0.000 claims description 7
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- DQJCDTNMLBYVAY-ZXXIYAEKSA-N (2S,5R,10R,13R)-16-{[(2R,3S,4R,5R)-3-{[(2S,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-5-(ethylamino)-6-hydroxy-2-(hydroxymethyl)oxan-4-yl]oxy}-5-(4-aminobutyl)-10-carbamoyl-2,13-dimethyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazaheptadecan-1-oic acid Chemical compound NCCCC[C@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)CC[C@H](C(N)=O)NC(=O)[C@@H](C)NC(=O)C(C)O[C@@H]1[C@@H](NCC)C(O)O[C@H](CO)[C@H]1O[C@H]1[C@H](NC(C)=O)[C@@H](O)[C@H](O)[C@@H](CO)O1 DQJCDTNMLBYVAY-ZXXIYAEKSA-N 0.000 claims description 6
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 6
- 206010009944 Colon cancer Diseases 0.000 claims description 6
- 102100037840 Dehydrogenase/reductase SDR family member 2, mitochondrial Human genes 0.000 claims description 6
- 108010015899 Glycopeptides Proteins 0.000 claims description 6
- 102000002068 Glycopeptides Human genes 0.000 claims description 6
- 101710188053 Protein D Proteins 0.000 claims description 6
- 101710132893 Resolvase Proteins 0.000 claims description 6
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 6
- 206010017758 gastric cancer Diseases 0.000 claims description 6
- 150000002632 lipids Chemical class 0.000 claims description 6
- 201000011549 stomach cancer Diseases 0.000 claims description 6
- DRHZYJAUECRAJM-DWSYSWFDSA-N (2s,3s,4s,5r,6r)-6-[[(3s,4s,4ar,6ar,6bs,8r,8ar,12as,14ar,14br)-8a-[(2s,3r,4s,5r,6r)-3-[(2s,3r,4s,5r,6s)-5-[(2s,3r,4s,5r)-4-[(2s,3r,4r)-3,4-dihydroxy-4-(hydroxymethyl)oxolan-2-yl]oxy-3,5-dihydroxyoxan-2-yl]oxy-3,4-dihydroxy-6-methyloxan-2-yl]oxy-5-[(3s,5s, Chemical compound O([C@H]1[C@H](O)[C@H](O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O1)O)O[C@H]1CC[C@]2(C)[C@H]3CC=C4[C@@H]5CC(C)(C)CC[C@@]5([C@@H](C[C@@]4(C)[C@]3(C)CC[C@H]2[C@@]1(C=O)C)O)C(=O)O[C@@H]1O[C@H](C)[C@@H]([C@@H]([C@H]1O[C@H]1[C@@H]([C@H](O)[C@@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@](O)(CO)CO3)O)[C@H](O)CO2)O)[C@H](C)O1)O)O)OC(=O)C[C@@H](O)C[C@H](OC(=O)C[C@@H](O)C[C@@H]([C@@H](C)CC)O[C@H]1[C@@H]([C@@H](O)[C@H](CO)O1)O)[C@@H](C)CC)C(O)=O)[C@@H]1OC[C@@H](O)[C@H](O)[C@H]1O DRHZYJAUECRAJM-DWSYSWFDSA-N 0.000 claims description 5
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 5
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 5
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 5
- 208000003445 Mouth Neoplasms Diseases 0.000 claims description 5
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 5
- 101710116435 Outer membrane protein Proteins 0.000 claims description 5
- 206010038389 Renal cancer Diseases 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 5
- 201000010881 cervical cancer Diseases 0.000 claims description 5
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 201000004101 esophageal cancer Diseases 0.000 claims description 5
- 201000010982 kidney cancer Diseases 0.000 claims description 5
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 claims description 5
- 201000007270 liver cancer Diseases 0.000 claims description 5
- 208000014018 liver neoplasm Diseases 0.000 claims description 5
- 229910052760 oxygen Chemical group 0.000 claims description 5
- 239000001301 oxygen Chemical group 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 claims description 4
- 206010005949 Bone cancer Diseases 0.000 claims description 4
- 208000018084 Bone neoplasm Diseases 0.000 claims description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 4
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 claims description 4
- 241000700605 Viruses Species 0.000 claims description 4
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 4
- 239000000412 dendrimer Substances 0.000 claims description 4
- 229920000736 dendritic polymer Polymers 0.000 claims description 4
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 claims description 4
- 229940031439 squalene Drugs 0.000 claims description 4
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 claims description 4
- 101710183389 Pneumolysin Proteins 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 230000000890 antigenic effect Effects 0.000 claims description 3
- 125000005587 carbonate group Chemical group 0.000 claims description 3
- 150000007942 carboxylates Chemical group 0.000 claims description 3
- YYGNTYWPHWGJRM-AAJYLUCBSA-N squalene Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CC\C=C(/C)CC\C=C(/C)CCC=C(C)C YYGNTYWPHWGJRM-AAJYLUCBSA-N 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 2
- 108010053187 Diphtheria Toxin Proteins 0.000 claims description 2
- 102000016607 Diphtheria Toxin Human genes 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- SNCZNSNPXMPCGN-UHFFFAOYSA-N butanediamide Chemical group NC(=O)CCC(N)=O SNCZNSNPXMPCGN-UHFFFAOYSA-N 0.000 claims description 2
- 231100000433 cytotoxic Toxicity 0.000 claims description 2
- 230000001472 cytotoxic effect Effects 0.000 claims description 2
- 125000001142 dicarboxylic acid group Chemical group 0.000 claims description 2
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical group NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 claims description 2
- 125000000101 thioether group Chemical group 0.000 claims description 2
- 241000237988 Patellidae Species 0.000 claims 1
- GNVMUORYQLCPJZ-UHFFFAOYSA-N carbamothioic s-acid Chemical group NC(S)=O GNVMUORYQLCPJZ-UHFFFAOYSA-N 0.000 claims 1
- 230000021615 conjugation Effects 0.000 claims 1
- 238000013467 fragmentation Methods 0.000 claims 1
- 238000006062 fragmentation reaction Methods 0.000 claims 1
- 108060003552 hemocyanin Proteins 0.000 claims 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 1
- 238000005481 NMR spectroscopy Methods 0.000 description 88
- 229960005486 vaccine Drugs 0.000 description 48
- 125000000623 heterocyclic group Chemical group 0.000 description 45
- 238000004896 high resolution mass spectrometry Methods 0.000 description 44
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 125000000217 alkyl group Chemical group 0.000 description 35
- 239000000243 solution Substances 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- 125000003118 aryl group Chemical group 0.000 description 25
- 125000000304 alkynyl group Chemical group 0.000 description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 125000003342 alkenyl group Chemical group 0.000 description 21
- 125000005647 linker group Chemical group 0.000 description 20
- 238000003786 synthesis reaction Methods 0.000 description 20
- 230000015572 biosynthetic process Effects 0.000 description 19
- 239000000047 product Substances 0.000 description 19
- 125000001424 substituent group Chemical group 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 16
- 108020005115 Pyruvate Kinase Proteins 0.000 description 16
- 102000013009 Pyruvate Kinase Human genes 0.000 description 16
- 238000002493 microarray Methods 0.000 description 15
- 241000283707 Capra Species 0.000 description 14
- 150000001720 carbohydrates Chemical class 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 239000000872 buffer Substances 0.000 description 12
- 125000004426 substituted alkynyl group Chemical group 0.000 description 12
- 102100038803 Somatotropin Human genes 0.000 description 11
- 125000002837 carbocyclic group Chemical group 0.000 description 11
- 239000008101 lactose Substances 0.000 description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- 235000018102 proteins Nutrition 0.000 description 11
- 125000005017 substituted alkenyl group Chemical group 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 10
- 102000009609 Pyrophosphatases Human genes 0.000 description 10
- 108010009413 Pyrophosphatases Proteins 0.000 description 10
- 230000004048 modification Effects 0.000 description 10
- 238000012986 modification Methods 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 210000002966 serum Anatomy 0.000 description 10
- 125000000547 substituted alkyl group Chemical group 0.000 description 10
- 235000000346 sugar Nutrition 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 9
- 102000004357 Transferases Human genes 0.000 description 9
- 108090000992 Transferases Proteins 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
- 125000001072 heteroaryl group Chemical group 0.000 description 9
- 150000002597 lactoses Chemical class 0.000 description 9
- 229960001592 paclitaxel Drugs 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 9
- 210000004881 tumor cell Anatomy 0.000 description 9
- 229930186217 Glycolipid Natural products 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- 229930012538 Paclitaxel Natural products 0.000 description 8
- 230000037396 body weight Effects 0.000 description 8
- 230000000295 complement effect Effects 0.000 description 8
- 238000003818 flash chromatography Methods 0.000 description 8
- 125000000524 functional group Chemical group 0.000 description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 description 8
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 8
- 150000003254 radicals Chemical class 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- HVCOBJNICQPDBP-UHFFFAOYSA-N 3-[3-[3,5-dihydroxy-6-methyl-4-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyoxan-2-yl]oxydecanoyloxy]decanoic acid;hydrate Chemical compound O.OC1C(OC(CC(=O)OC(CCCCCCC)CC(O)=O)CCCCCCC)OC(C)C(O)C1OC1C(O)C(O)C(O)C(C)O1 HVCOBJNICQPDBP-UHFFFAOYSA-N 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- 230000027455 binding Effects 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 229940088598 enzyme Drugs 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- 150000002430 hydrocarbons Chemical group 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 230000008929 regeneration Effects 0.000 description 7
- 238000011069 regeneration method Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 102100037777 Galactokinase Human genes 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 6
- MBLBDJOUHNCFQT-UHFFFAOYSA-N N-acetyl-D-galactosamine Natural products CC(=O)NC(C=O)C(O)C(O)C(O)CO MBLBDJOUHNCFQT-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 6
- 101001066237 Treponema pallidum (strain Nichols) Putative galactokinase Proteins 0.000 description 6
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 6
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000013543 active substance Substances 0.000 description 6
- 239000002246 antineoplastic agent Substances 0.000 description 6
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- 239000002504 physiological saline solution Substances 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 230000002441 reversible effect Effects 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 description 5
- 102000009617 Inorganic Pyrophosphatase Human genes 0.000 description 5
- 108010009595 Inorganic Pyrophosphatase Proteins 0.000 description 5
- 206010025323 Lymphomas Diseases 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 210000001744 T-lymphocyte Anatomy 0.000 description 5
- 239000007983 Tris buffer Substances 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 5
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 235000014633 carbohydrates Nutrition 0.000 description 5
- 125000003636 chemical group Chemical group 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000000684 flow cytometry Methods 0.000 description 5
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 5
- 125000001153 fluoro group Chemical group F* 0.000 description 5
- 230000014509 gene expression Effects 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 150000002367 halogens Chemical class 0.000 description 5
- 229960002411 imatinib Drugs 0.000 description 5
- 230000036039 immunity Effects 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 108010045069 keyhole-limpet hemocyanin Proteins 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 229920001542 oligosaccharide Polymers 0.000 description 5
- 150000002482 oligosaccharides Chemical class 0.000 description 5
- 229920001282 polysaccharide Polymers 0.000 description 5
- 239000005017 polysaccharide Substances 0.000 description 5
- 238000010186 staining Methods 0.000 description 5
- 230000002194 synthesizing effect Effects 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 4
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 4
- 239000012114 Alexa Fluor 647 Substances 0.000 description 4
- 101000638915 Arabidopsis thaliana UDP-sugar pyrophosphorylase Proteins 0.000 description 4
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 4
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 4
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 4
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 4
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 4
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 4
- 208000015634 Rectal Neoplasms Diseases 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 208000000453 Skin Neoplasms Diseases 0.000 description 4
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 4
- HSCJRCZFDFQWRP-ABVWGUQPSA-N UDP-alpha-D-galactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1OP(O)(=O)OP(O)(=O)OC[C@@H]1[C@@H](O)[C@@H](O)[C@H](N2C(NC(=O)C=C2)=O)O1 HSCJRCZFDFQWRP-ABVWGUQPSA-N 0.000 description 4
- HSCJRCZFDFQWRP-UHFFFAOYSA-N Uridindiphosphoglukose Natural products OC1C(O)C(O)C(CO)OC1OP(O)(=O)OP(O)(=O)OCC1C(O)C(O)C(N2C(NC(=O)C=C2)=O)O1 HSCJRCZFDFQWRP-UHFFFAOYSA-N 0.000 description 4
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 4
- 239000000370 acceptor Substances 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 230000007402 cytotoxic response Effects 0.000 description 4
- 231100000135 cytotoxicity Toxicity 0.000 description 4
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 238000004108 freeze drying Methods 0.000 description 4
- 229930182830 galactose Natural products 0.000 description 4
- 238000005227 gel permeation chromatography Methods 0.000 description 4
- 230000003053 immunization Effects 0.000 description 4
- 239000000568 immunological adjuvant Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 4
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 4
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 4
- 229960001972 panitumumab Drugs 0.000 description 4
- 206010038038 rectal cancer Diseases 0.000 description 4
- 201000001275 rectum cancer Diseases 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 229960004641 rituximab Drugs 0.000 description 4
- 201000000849 skin cancer Diseases 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- 239000013598 vector Substances 0.000 description 4
- 239000011534 wash buffer Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 3
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 3
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 3
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 3
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 3
- JOOXCMJARBKPKM-UHFFFAOYSA-M 4-oxopentanoate Chemical compound CC(=O)CCC([O-])=O JOOXCMJARBKPKM-UHFFFAOYSA-M 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 201000003076 Angiosarcoma Diseases 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 108010006654 Bleomycin Proteins 0.000 description 3
- 125000005915 C6-C14 aryl group Chemical group 0.000 description 3
- 0 CC(C)(C)OC(NCCCCCO[C@@](C(C1O)O)OC(C*)[C@]1O[C@@](C(C1O)O)OC2[C@@]1OC(c1ccccc1)OC2)=O Chemical compound CC(C)(C)OC(NCCCCCO[C@@](C(C1O)O)OC(C*)[C@]1O[C@@](C(C1O)O)OC2[C@@]1OC(c1ccccc1)OC2)=O 0.000 description 3
- 206010014733 Endometrial cancer Diseases 0.000 description 3
- 206010014759 Endometrial neoplasm Diseases 0.000 description 3
- 108090000288 Glycoproteins Proteins 0.000 description 3
- 102000003886 Glycoproteins Human genes 0.000 description 3
- 208000001258 Hemangiosarcoma Diseases 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 3
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 3
- 102100035838 Lactosylceramide 4-alpha-galactosyltransferase Human genes 0.000 description 3
- FZLJPEPAYPUMMR-FMDGEEDCSA-N N-acetyl-alpha-D-glucosamine 1-phosphate Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OP(O)(O)=O FZLJPEPAYPUMMR-FMDGEEDCSA-N 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 241001494479 Pecora Species 0.000 description 3
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 description 3
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 3
- 102100029677 Trehalase Human genes 0.000 description 3
- 108010087472 Trehalase Proteins 0.000 description 3
- LFTYTUAZOPRMMI-NESSUJCYSA-N UDP-N-acetyl-alpha-D-galactosamine Chemical compound O1[C@H](CO)[C@H](O)[C@H](O)[C@@H](NC(=O)C)[C@H]1O[P@](O)(=O)O[P@](O)(=O)OC[C@@H]1[C@@H](O)[C@@H](O)[C@H](N2C(NC(=O)C=C2)=O)O1 LFTYTUAZOPRMMI-NESSUJCYSA-N 0.000 description 3
- 108010070808 UDP-galactose-lactosylceramide alpha 1-4-galactosyltransferase Proteins 0.000 description 3
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 3
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 3
- 229960000397 bevacizumab Drugs 0.000 description 3
- 229960005395 cetuximab Drugs 0.000 description 3
- 229920001429 chelating resin Polymers 0.000 description 3
- PIQCTGMSNWUMAF-UHFFFAOYSA-N chembl522892 Chemical compound C1CN(C)CCN1C1=CC=C(NC(=N2)C=3C(NC4=CC=CC(F)=C4C=3N)=O)C2=C1 PIQCTGMSNWUMAF-UHFFFAOYSA-N 0.000 description 3
- 229960004630 chlorambucil Drugs 0.000 description 3
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 3
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 3
- 238000002648 combination therapy Methods 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 229940127089 cytotoxic agent Drugs 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 229960003901 dacarbazine Drugs 0.000 description 3
- 229960002448 dasatinib Drugs 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 208000025750 heavy chain disease Diseases 0.000 description 3
- 210000002865 immune cell Anatomy 0.000 description 3
- 230000002163 immunogen Effects 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 229960004891 lapatinib Drugs 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 229960000485 methotrexate Drugs 0.000 description 3
- 201000005962 mycosis fungoides Diseases 0.000 description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 230000003472 neutralizing effect Effects 0.000 description 3
- 239000002773 nucleotide Substances 0.000 description 3
- 125000003729 nucleotide group Chemical group 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- 108700027936 paclitaxel poliglumex Proteins 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- WUWDLXZGHZSWQZ-WQLSENKSSA-N semaxanib Chemical compound N1C(C)=CC(C)=C1\C=C/1C2=CC=CC=C2NC\1=O WUWDLXZGHZSWQZ-WQLSENKSSA-N 0.000 description 3
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 150000008163 sugars Chemical class 0.000 description 3
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 3
- 229960000235 temsirolimus Drugs 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 150000003625 trehaloses Chemical class 0.000 description 3
- 238000002604 ultrasonography Methods 0.000 description 3
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 3
- 229940045145 uridine Drugs 0.000 description 3
- 229960000241 vandetanib Drugs 0.000 description 3
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 3
- 229950000578 vatalanib Drugs 0.000 description 3
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 3
- ZPUHVPYXSITYDI-HEUWMMRCSA-N xyotax Chemical compound OC(=O)[C@@H](N)CCC(O)=O.O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 ZPUHVPYXSITYDI-HEUWMMRCSA-N 0.000 description 3
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- PMIODTBPFKLUMF-UHFFFAOYSA-N (2-nitrophenyl)methyl hydrogen carbonate Chemical compound OC(=O)OCC1=CC=CC=C1[N+]([O-])=O PMIODTBPFKLUMF-UHFFFAOYSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 description 2
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 2
- 125000001917 2,4-dinitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1*)[N+]([O-])=O)[N+]([O-])=O 0.000 description 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 2
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 2
- UJRMHFPTLFNSTA-UHFFFAOYSA-N 2-chloro-2,2-diphenylacetic acid Chemical compound C=1C=CC=CC=1C(Cl)(C(=O)O)C1=CC=CC=C1 UJRMHFPTLFNSTA-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 2
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 2
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 2
- XXJWYDDUDKYVKI-UHFFFAOYSA-N 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline Chemical compound COC1=CC2=C(OC=3C(=C4C=C(C)NC4=CC=3)F)N=CN=C2C=C1OCCCN1CCCC1 XXJWYDDUDKYVKI-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- SRSGVKWWVXWSJT-ATVHPVEESA-N 5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-n-(2-pyrrolidin-1-ylethyl)-1h-pyrrole-3-carboxamide Chemical compound CC=1NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C(C)C=1C(=O)NCCN1CCCC1 SRSGVKWWVXWSJT-ATVHPVEESA-N 0.000 description 2
- BUROJSBIWGDYCN-GAUTUEMISA-N AP 23573 Chemical compound C1C[C@@H](OP(C)(C)=O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 BUROJSBIWGDYCN-GAUTUEMISA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- 208000012791 Alpha-heavy chain disease Diseases 0.000 description 2
- 102100036013 Antigen-presenting glycoprotein CD1d Human genes 0.000 description 2
- 206010073360 Appendix cancer Diseases 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 2
- 208000003950 B-cell lymphoma Diseases 0.000 description 2
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 2
- 206010004146 Basal cell carcinoma Diseases 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 2
- 201000004085 CLL/SLL Diseases 0.000 description 2
- 108010034055 CRM45 fragment of diphtheria toxin Proteins 0.000 description 2
- 206010007275 Carcinoid tumour Diseases 0.000 description 2
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 2
- 229960005500 DHA-paclitaxel Drugs 0.000 description 2
- 108010092160 Dactinomycin Proteins 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 241000283086 Equidae Species 0.000 description 2
- 208000032027 Essential Thrombocythemia Diseases 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 108010051696 Growth Hormone Proteins 0.000 description 2
- 102000002268 Hexosaminidases Human genes 0.000 description 2
- 108010000540 Hexosaminidases Proteins 0.000 description 2
- 208000017604 Hodgkin disease Diseases 0.000 description 2
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 2
- 101000716121 Homo sapiens Antigen-presenting glycoprotein CD1d Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010048643 Hypereosinophilic syndrome Diseases 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 208000007866 Immunoproliferative Small Intestinal Disease Diseases 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 2
- 208000007766 Kaposi sarcoma Diseases 0.000 description 2
- 206010023347 Keratoacanthoma Diseases 0.000 description 2
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 2
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 2
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 2
- 208000018142 Leiomyosarcoma Diseases 0.000 description 2
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 2
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 description 2
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- 208000014767 Myeloproliferative disease Diseases 0.000 description 2
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 description 2
- OVRNDRQMDRJTHS-CBQIKETKSA-N N-Acetyl-D-Galactosamine Chemical compound CC(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-CBQIKETKSA-N 0.000 description 2
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- 208000009905 Neurofibromatoses Diseases 0.000 description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 208000027190 Peripheral T-cell lymphomas Diseases 0.000 description 2
- 208000031839 Peripheral nerve sheath tumour malignant Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 108020004511 Recombinant DNA Proteins 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 206010041067 Small cell lung cancer Diseases 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 241000282898 Sus scrofa Species 0.000 description 2
- 208000031673 T-Cell Cutaneous Lymphoma Diseases 0.000 description 2
- 208000031672 T-Cell Peripheral Lymphoma Diseases 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 description 2
- 239000003819 Toceranib Substances 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 108050008412 UDP-sugar pyrophosphorylases Proteins 0.000 description 2
- 102000000102 UDP-sugar pyrophosphorylases Human genes 0.000 description 2
- 208000015778 Undifferentiated pleomorphic sarcoma Diseases 0.000 description 2
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 2
- 229940122803 Vinca alkaloid Drugs 0.000 description 2
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- LQEBEXMHBLQMDB-UHFFFAOYSA-N [[5-(2-amino-6-oxo-3h-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] (3,4,5-trihydroxy-6-methyloxan-2-yl) hydrogen phosphate Chemical compound OC1C(O)C(O)C(C)OC1OP(O)(=O)OP(O)(=O)OCC1C(O)C(O)C(N2C3=C(C(N=C(N)N3)=O)N=C2)O1 LQEBEXMHBLQMDB-UHFFFAOYSA-N 0.000 description 2
- 208000017733 acquired polycythemia vera Diseases 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 208000009956 adenocarcinoma Diseases 0.000 description 2
- 239000000362 adenosine triphosphatase inhibitor Substances 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 208000025751 alpha chain disease Diseases 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 229940045799 anthracyclines and related substance Drugs 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 208000021780 appendiceal neoplasm Diseases 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 2
- 229940120638 avastin Drugs 0.000 description 2
- 210000003050 axon Anatomy 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 125000006267 biphenyl group Chemical group 0.000 description 2
- IEPBPSSCIZTJIF-UHFFFAOYSA-N bis(2,2,2-trichloroethyl) carbonate Chemical compound ClC(Cl)(Cl)COC(=O)OCC(Cl)(Cl)Cl IEPBPSSCIZTJIF-UHFFFAOYSA-N 0.000 description 2
- JZUVESQYEHERMD-UHFFFAOYSA-N bis[(4-nitrophenyl)methyl] carbonate Chemical compound C1=CC([N+](=O)[O-])=CC=C1COC(=O)OCC1=CC=C([N+]([O-])=O)C=C1 JZUVESQYEHERMD-UHFFFAOYSA-N 0.000 description 2
- 229960001561 bleomycin Drugs 0.000 description 2
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 208000002458 carcinoid tumor Diseases 0.000 description 2
- 229930188550 carminomycin Natural products 0.000 description 2
- XREUEWVEMYWFFA-CSKJXFQVSA-N carminomycin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XREUEWVEMYWFFA-CSKJXFQVSA-N 0.000 description 2
- XREUEWVEMYWFFA-UHFFFAOYSA-N carminomycin I Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XREUEWVEMYWFFA-UHFFFAOYSA-N 0.000 description 2
- 229950001725 carubicin Drugs 0.000 description 2
- 229960002412 cediranib Drugs 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000006143 cell culture medium Substances 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- JROFGZPOBKIAEW-HAQNSBGRSA-N chembl3120215 Chemical compound N1C=2C(OC)=CC=CC=2C=C1C(=C1C(N)=NC=NN11)N=C1[C@H]1CC[C@H](C(O)=O)CC1 JROFGZPOBKIAEW-HAQNSBGRSA-N 0.000 description 2
- 229910052729 chemical element Inorganic materials 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 208000023738 chronic lymphocytic leukemia/small lymphocytic lymphoma Diseases 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125810 compound 20 Drugs 0.000 description 2
- 229940126086 compound 21 Drugs 0.000 description 2
- 229940126208 compound 22 Drugs 0.000 description 2
- 229940125833 compound 23 Drugs 0.000 description 2
- 229940125961 compound 24 Drugs 0.000 description 2
- 229940125846 compound 25 Drugs 0.000 description 2
- 229940125851 compound 27 Drugs 0.000 description 2
- 229940127204 compound 29 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000003431 cross linking reagent Substances 0.000 description 2
- LDHQCZJRKDOVOX-NSCUHMNNSA-M crotonate Chemical compound C\C=C\C([O-])=O LDHQCZJRKDOVOX-NSCUHMNNSA-M 0.000 description 2
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 description 2
- 229960004397 cyclophosphamide Drugs 0.000 description 2
- 210000004443 dendritic cell Anatomy 0.000 description 2
- LRCZQSDQZJBHAF-PUBGEWHCSA-N dha-paclitaxel Chemical compound N([C@H]([C@@H](OC(=O)CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC)C(=O)O[C@@H]1C(=C2[C@@H](OC(C)=O)C(=O)[C@]3(C)[C@@H](O)C[C@H]4OC[C@]4([C@H]3[C@H](OC(=O)C=3C=CC=CC=3)[C@](C2(C)C)(O)C1)OC(C)=O)C)C=1C=CC=CC=1)C(=O)C1=CC=CC=C1 LRCZQSDQZJBHAF-PUBGEWHCSA-N 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 2
- 208000017055 digestive system neuroendocrine neoplasm Diseases 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000002500 effect on skin Effects 0.000 description 2
- 229940082789 erbitux Drugs 0.000 description 2
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 2
- 229960001842 estramustine Drugs 0.000 description 2
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 2
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 229960005167 everolimus Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 235000013312 flour Nutrition 0.000 description 2
- 229960000390 fludarabine Drugs 0.000 description 2
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 2
- 229960003297 gemtuzumab ozogamicin Drugs 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 2
- 229930182470 glycoside Natural products 0.000 description 2
- 239000000122 growth hormone Substances 0.000 description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 2
- 201000009277 hairy cell leukemia Diseases 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 201000005787 hematologic cancer Diseases 0.000 description 2
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 2
- 229940022353 herceptin Drugs 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000008105 immune reaction Effects 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 238000002649 immunization Methods 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000002348 inosinate dehydrogenase inhibitor Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 201000009020 malignant peripheral nerve sheath tumor Diseases 0.000 description 2
- 208000020968 mature T-cell and NK-cell non-Hodgkin lymphoma Diseases 0.000 description 2
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 2
- 229960001924 melphalan Drugs 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 2
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 2
- 238000010369 molecular cloning Methods 0.000 description 2
- 150000002772 monosaccharides Chemical class 0.000 description 2
- 229940031348 multivalent vaccine Drugs 0.000 description 2
- 206010028537 myelofibrosis Diseases 0.000 description 2
- VQSRKMNBWMHJKY-YTEVENLXSA-N n-[3-[(4ar,7as)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide Chemical compound C1=NC(OC)=CN=C1C(=O)NC1=CC=C(F)C([C@@]23[C@@H](CN(C2)C=2N=CC(F)=CN=2)CSC(N)=N3)=C1 VQSRKMNBWMHJKY-YTEVENLXSA-N 0.000 description 2
- 210000000581 natural killer T-cell Anatomy 0.000 description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 201000002120 neuroendocrine carcinoma Diseases 0.000 description 2
- 201000004931 neurofibromatosis Diseases 0.000 description 2
- 208000029974 neurofibrosarcoma Diseases 0.000 description 2
- 229960001346 nilotinib Drugs 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 201000002740 oral squamous cell carcinoma Diseases 0.000 description 2
- DPBLXKKOBLCELK-UHFFFAOYSA-N pentan-1-amine Chemical compound CCCCCN DPBLXKKOBLCELK-UHFFFAOYSA-N 0.000 description 2
- 238000009521 phase II clinical trial Methods 0.000 description 2
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical compound OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 238000002428 photodynamic therapy Methods 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 208000037244 polycythemia vera Diseases 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 description 2
- 208000003476 primary myelofibrosis Diseases 0.000 description 2
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 229960001302 ridaforolimus Drugs 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229950003647 semaxanib Drugs 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- 229960002930 sirolimus Drugs 0.000 description 2
- 208000000587 small cell lung carcinoma Diseases 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 229960001796 sunitinib Drugs 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 229940069905 tasigna Drugs 0.000 description 2
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- 201000002510 thyroid cancer Diseases 0.000 description 2
- 208000030045 thyroid gland papillary carcinoma Diseases 0.000 description 2
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 2
- 229960005267 tositumomab Drugs 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 229960000575 trastuzumab Drugs 0.000 description 2
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 2
- 150000004043 trisaccharides Chemical class 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- AADVCYNFEREWOS-UHFFFAOYSA-N (+)-DDM Natural products C=CC=CC(C)C(OC(N)=O)C(C)C(O)C(C)CC(C)=CC(C)C(O)C(C)C=CC(O)CC1OC(=O)C(C)C(O)C1C AADVCYNFEREWOS-UHFFFAOYSA-N 0.000 description 1
- QYYZXEPEVBXNNA-QGZVFWFLSA-N (1R)-2-acetyl-N-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl]-5-methylsulfonyl-1,3-dihydroisoindole-1-carboxamide Chemical compound C(C)(=O)N1[C@H](C2=CC=C(C=C2C1)S(=O)(=O)C)C(=O)NC1=CC=C(C=C1)C(C(F)(F)F)(C(F)(F)F)O QYYZXEPEVBXNNA-QGZVFWFLSA-N 0.000 description 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- KGWWHPZQLVVAPT-STTJLUEPSA-N (2r,3r)-2,3-dihydroxybutanedioic acid;6-(4-methylpiperazin-1-yl)-n-(5-methyl-1h-pyrazol-3-yl)-2-[(e)-2-phenylethenyl]pyrimidin-4-amine Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1CN(C)CCN1C1=CC(NC2=NNC(C)=C2)=NC(\C=C\C=2C=CC=CC=2)=N1 KGWWHPZQLVVAPT-STTJLUEPSA-N 0.000 description 1
- YOVVNQKCSKSHKT-HNNXBMFYSA-N (2s)-1-[4-[[2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-yl]methyl]piperazin-1-yl]-2-hydroxypropan-1-one Chemical compound C1CN(C(=O)[C@@H](O)C)CCN1CC1=C(C)C2=NC(C=3C=NC(N)=NC=3)=NC(N3CCOCC3)=C2S1 YOVVNQKCSKSHKT-HNNXBMFYSA-N 0.000 description 1
- MCEHFIXEKNKSRW-LBPRGKRZSA-N (2s)-2-[[3,5-dichloro-4-[(2,4-diaminopteridin-6-yl)methyl-methylamino]benzoyl]amino]pentanedioic acid Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=C(Cl)C=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1Cl MCEHFIXEKNKSRW-LBPRGKRZSA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- ZTESKPLFUKCHOF-UHFFFAOYSA-N (3,4-dimethoxyphenyl)methyl hydrogen carbonate Chemical compound COC1=CC=C(COC(O)=O)C=C1OC ZTESKPLFUKCHOF-UHFFFAOYSA-N 0.000 description 1
- HZFLPRPFCHEBPQ-UHFFFAOYSA-N (4-methoxyphenyl)methyl hydrogen carbonate Chemical compound COC1=CC=C(COC(O)=O)C=C1 HZFLPRPFCHEBPQ-UHFFFAOYSA-N 0.000 description 1
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000006545 (C1-C9) alkyl group Chemical group 0.000 description 1
- 125000006649 (C2-C20) alkynyl group Chemical group 0.000 description 1
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 1
- YYEYJWOZXLZHEO-BENRWUELSA-N (Z)-11-methyl-N-(methylsulfonyl)dodec-2-enamide Chemical compound CC(C)CCCCCCC\C=C/C(=O)NS(C)(=O)=O YYEYJWOZXLZHEO-BENRWUELSA-N 0.000 description 1
- LKUWQWDAIWXHIY-XOMXBQTJSA-N (e)-2-methylbut-2-enoic acid Chemical compound C\C=C(/C)C(O)=O.C\C=C(/C)C(O)=O LKUWQWDAIWXHIY-XOMXBQTJSA-N 0.000 description 1
- ZOJKRWXDNYZASL-NSCUHMNNSA-N (e)-4-methoxybut-2-enoic acid Chemical compound COC\C=C\C(O)=O ZOJKRWXDNYZASL-NSCUHMNNSA-N 0.000 description 1
- VZXTWGWHSMCWGA-UHFFFAOYSA-N 1,3,5-triazine-2,4-diamine Chemical group NC1=NC=NC(N)=N1 VZXTWGWHSMCWGA-UHFFFAOYSA-N 0.000 description 1
- VAYTZRYEBVHVLE-UHFFFAOYSA-N 1,3-dioxol-2-one Chemical compound O=C1OC=CO1 VAYTZRYEBVHVLE-UHFFFAOYSA-N 0.000 description 1
- SWQQELWGJDXCFT-PNHWDRBUSA-N 1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-ethynylimidazole-4-carboxamide Chemical compound C#CC1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 SWQQELWGJDXCFT-PNHWDRBUSA-N 0.000 description 1
- SPMVMDHWKHCIDT-UHFFFAOYSA-N 1-[2-chloro-4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-3-(5-methyl-3-isoxazolyl)urea Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC=1C=C(C)ON=1 SPMVMDHWKHCIDT-UHFFFAOYSA-N 0.000 description 1
- MNCMBBIFTVWHIP-UHFFFAOYSA-N 1-anthracen-9-yl-2,2,2-trifluoroethanone Chemical group C1=CC=C2C(C(=O)C(F)(F)F)=C(C=CC=C3)C3=CC2=C1 MNCMBBIFTVWHIP-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- FFFIRKXTFQCCKJ-UHFFFAOYSA-M 2,4,6-trimethylbenzoate Chemical compound CC1=CC(C)=C(C([O-])=O)C(C)=C1 FFFIRKXTFQCCKJ-UHFFFAOYSA-M 0.000 description 1
- NXRGKFVQYZGDIY-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1.CC1=CC=CC(C)=N1 NXRGKFVQYZGDIY-UHFFFAOYSA-N 0.000 description 1
- YURLCYGZYWDCHL-UHFFFAOYSA-N 2-(2,6-dichloro-4-methylphenoxy)acetic acid Chemical compound CC1=CC(Cl)=C(OCC(O)=O)C(Cl)=C1 YURLCYGZYWDCHL-UHFFFAOYSA-N 0.000 description 1
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- RNAMYOYQYRYFQY-UHFFFAOYSA-N 2-(4,4-difluoropiperidin-1-yl)-6-methoxy-n-(1-propan-2-ylpiperidin-4-yl)-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-amine Chemical compound N1=C(N2CCC(F)(F)CC2)N=C2C=C(OCCCN3CCCC3)C(OC)=CC2=C1NC1CCN(C(C)C)CC1 RNAMYOYQYRYFQY-UHFFFAOYSA-N 0.000 description 1
- TYYAMZMDZWXHHA-UHFFFAOYSA-N 2-(dibromomethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(Br)Br TYYAMZMDZWXHHA-UHFFFAOYSA-N 0.000 description 1
- 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 0.000 description 1
- QXQMENSTZKYZCE-UHFFFAOYSA-N 2-[2,4-bis(2-methylbutan-2-yl)phenoxy]acetic acid Chemical compound CCC(C)(C)C1=CC=C(OCC(O)=O)C(C(C)(C)CC)=C1 QXQMENSTZKYZCE-UHFFFAOYSA-N 0.000 description 1
- XTRFZKJEMAVUIK-UHFFFAOYSA-N 2-[2,6-dichloro-4-(2,4,4-trimethylpentan-2-yl)phenoxy]acetic acid Chemical compound CC(C)(C)CC(C)(C)C1=CC(Cl)=C(OCC(O)=O)C(Cl)=C1 XTRFZKJEMAVUIK-UHFFFAOYSA-N 0.000 description 1
- PDMUGYOXRHVNMO-UHFFFAOYSA-N 2-[4-[3-(6-quinolinylmethyl)-5-triazolo[4,5-b]pyrazinyl]-1-pyrazolyl]ethanol Chemical compound C1=NN(CCO)C=C1C1=CN=C(N=NN2CC=3C=C4C=CC=NC4=CC=3)C2=N1 PDMUGYOXRHVNMO-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-GASJEMHNSA-N 2-amino-2-deoxy-D-galactopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O MSWZFWKMSRAUBD-GASJEMHNSA-N 0.000 description 1
- SHHKMWMIKILKQW-UHFFFAOYSA-N 2-formylbenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1C=O SHHKMWMIKILKQW-UHFFFAOYSA-N 0.000 description 1
- CJNZAXGUTKBIHP-UHFFFAOYSA-M 2-iodobenzoate Chemical compound [O-]C(=O)C1=CC=CC=C1I CJNZAXGUTKBIHP-UHFFFAOYSA-M 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- LDZNCSVWVMBVST-UHFFFAOYSA-N 2-trimethylsilylethyl hydrogen carbonate Chemical compound C[Si](C)(C)CCOC(O)=O LDZNCSVWVMBVST-UHFFFAOYSA-N 0.000 description 1
- IPHPFXHEWMVPQA-UHFFFAOYSA-N 2-triphenylphosphaniumylethyl carbonate Chemical compound C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(CCOC(=O)[O-])C1=CC=CC=C1 IPHPFXHEWMVPQA-UHFFFAOYSA-N 0.000 description 1
- GPVOTFQILZVCFP-UHFFFAOYSA-N 2-trityloxyacetic acid Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(OCC(=O)O)C1=CC=CC=C1 GPVOTFQILZVCFP-UHFFFAOYSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- FGTCROZDHDSNIO-UHFFFAOYSA-N 3-(4-quinolinylmethylamino)-N-[4-(trifluoromethoxy)phenyl]-2-thiophenecarboxamide Chemical compound C1=CC(OC(F)(F)F)=CC=C1NC(=O)C1=C(NCC=2C3=CC=CC=C3N=CC=2)C=CS1 FGTCROZDHDSNIO-UHFFFAOYSA-N 0.000 description 1
- 125000004917 3-methyl-2-butyl group Chemical group CC(C(C)*)C 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-M 3-phenylpropionate Chemical compound [O-]C(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-M 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- NDRAHSMAGKWWFZ-UHFFFAOYSA-N 4-(methylsulfanylmethoxy)butanoic acid Chemical compound CSCOCCCC(O)=O NDRAHSMAGKWWFZ-UHFFFAOYSA-N 0.000 description 1
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 description 1
- WAGMYTXJRVPMGW-UHFFFAOYSA-N 4-azidobutanoic acid Chemical compound OC(=O)CCCN=[N+]=[N-] WAGMYTXJRVPMGW-UHFFFAOYSA-N 0.000 description 1
- FDLQPQXYEBSYAB-UHFFFAOYSA-N 4-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1.COC1=CC=C(C=O)C=C1 FDLQPQXYEBSYAB-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- KHKJLJHJTQRHSA-UHFFFAOYSA-N 4-methyl-4-nitropentanoic acid Chemical compound [O-][N+](=O)C(C)(C)CCC(O)=O KHKJLJHJTQRHSA-UHFFFAOYSA-N 0.000 description 1
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 1
- GTVVZTAFGPQSPC-UHFFFAOYSA-N 4-nitrophenylalanine Chemical compound OC(=O)C(N)CC1=CC=C([N+]([O-])=O)C=C1 GTVVZTAFGPQSPC-UHFFFAOYSA-N 0.000 description 1
- NNJMFJSKMRYHSR-UHFFFAOYSA-M 4-phenylbenzoate Chemical compound C1=CC(C(=O)[O-])=CC=C1C1=CC=CC=C1 NNJMFJSKMRYHSR-UHFFFAOYSA-M 0.000 description 1
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- FUXVKZWTXQUGMW-FQEVSTJZSA-N 9-Aminocamptothecin Chemical compound C1=CC(N)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 FUXVKZWTXQUGMW-FQEVSTJZSA-N 0.000 description 1
- 229940121819 ATPase inhibitor Drugs 0.000 description 1
- KVLFRAWTRWDEDF-IRXDYDNUSA-N AZD-8055 Chemical compound C1=C(CO)C(OC)=CC=C1C1=CC=C(C(=NC(=N2)N3[C@H](COCC3)C)N3[C@H](COCC3)C)C2=N1 KVLFRAWTRWDEDF-IRXDYDNUSA-N 0.000 description 1
- 108700016155 Acyl transferases Proteins 0.000 description 1
- 102000057234 Acyl transferases Human genes 0.000 description 1
- 102100031260 Acyl-coenzyme A thioesterase THEM4 Human genes 0.000 description 1
- 208000036832 Adenocarcinoma of ovary Diseases 0.000 description 1
- 206010001197 Adenocarcinoma of the cervix Diseases 0.000 description 1
- 208000034246 Adenocarcinoma of the cervix uteri Diseases 0.000 description 1
- 208000036764 Adenocarcinoma of the esophagus Diseases 0.000 description 1
- ULXXDDBFHOBEHA-ONEGZZNKSA-N Afatinib Chemical compound N1=CN=C2C=C(OC3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-ONEGZZNKSA-N 0.000 description 1
- 108010012934 Albumin-Bound Paclitaxel Proteins 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 239000012103 Alexa Fluor 488 Substances 0.000 description 1
- 101710098620 Alpha-1,2-fucosyltransferase Proteins 0.000 description 1
- 206010061424 Anal cancer Diseases 0.000 description 1
- 206010073478 Anaplastic large-cell lymphoma Diseases 0.000 description 1
- 208000007860 Anus Neoplasms Diseases 0.000 description 1
- 102000015790 Asparaginase Human genes 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 208000036170 B-Cell Marginal Zone Lymphoma Diseases 0.000 description 1
- YUXMAKUNSXIEKN-BTJKTKAUSA-N BGT226 Chemical compound OC(=O)\C=C/C(O)=O.C1=NC(OC)=CC=C1C1=CC=C(N=CC2=C3N(C=4C=C(C(N5CCNCC5)=CC=4)C(F)(F)F)C(=O)N2C)C3=C1 YUXMAKUNSXIEKN-BTJKTKAUSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010004593 Bile duct cancer Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- 208000011691 Burkitt lymphomas Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 description 1
- 125000003358 C2-C20 alkenyl group Chemical group 0.000 description 1
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 description 1
- GTNTZHZBKDWTBH-CXMXMZLESA-N CO[C@@H](C(C1O)O)OC(CO)[C@H]1O[C@@H](C(C1O)O)OC2[C@@H]1OC(c1ccccc1)OC2 Chemical compound CO[C@@H](C(C1O)O)OC(CO)[C@H]1O[C@@H](C(C1O)O)OC2[C@@H]1OC(c1ccccc1)OC2 GTNTZHZBKDWTBH-CXMXMZLESA-N 0.000 description 1
- 108010053406 CRM 107 Proteins 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- 102000004612 Calcium-Transporting ATPases Human genes 0.000 description 1
- 108010017954 Calcium-Transporting ATPases Proteins 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 229940123587 Cell cycle inhibitor Drugs 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000005944 Chlorpyrifos Substances 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- 201000009047 Chordoma Diseases 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010052360 Colorectal adenocarcinoma Diseases 0.000 description 1
- 208000009798 Craniopharyngioma Diseases 0.000 description 1
- FMGYKKMPNATWHP-UHFFFAOYSA-N Cyperquat Chemical compound C1=C[N+](C)=CC=C1C1=CC=CC=C1 FMGYKKMPNATWHP-UHFFFAOYSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- WVXNSAVVKYZVOE-UHFFFAOYSA-N DCC-2036 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3N(N=C(C=3)C(C)(C)C)C=3C=C4C=CC=NC4=CC=3)=CC=2)=C1 WVXNSAVVKYZVOE-UHFFFAOYSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 102100024746 Dihydrofolate reductase Human genes 0.000 description 1
- AADVCYNFEREWOS-OBRABYBLSA-N Discodermolide Chemical compound C=C\C=C/[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O)[C@@H](C)C\C(C)=C/[C@H](C)[C@@H](O)[C@@H](C)\C=C/[C@@H](O)C[C@@H]1OC(=O)[C@H](C)[C@@H](O)[C@H]1C AADVCYNFEREWOS-OBRABYBLSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 208000002460 Enteropathy-Associated T-Cell Lymphoma Diseases 0.000 description 1
- 206010014950 Eosinophilia Diseases 0.000 description 1
- 206010014967 Ependymoma Diseases 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 244000089409 Erythrina poeppigiana Species 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 108010045674 Fucose-1-phosphate guanylyltransferase Proteins 0.000 description 1
- 102100037047 Fucose-1-phosphate guanylyltransferase Human genes 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 102100036250 GPI mannosyltransferase 4 Human genes 0.000 description 1
- 102000048120 Galactokinases Human genes 0.000 description 1
- 108700023157 Galactokinases Proteins 0.000 description 1
- 208000022072 Gallbladder Neoplasms Diseases 0.000 description 1
- 201000003741 Gastrointestinal carcinoma Diseases 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 102100039847 Globoside alpha-1,3-N-acetylgalactosaminyltransferase 1 Human genes 0.000 description 1
- 108700023372 Glycosyltransferases Proteins 0.000 description 1
- 102000051366 Glycosyltransferases Human genes 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- VJLLLMIZEJJZTE-VNQXHBPZSA-N HexCer(d18:1/16:0) Chemical class CCCCCCCCCCCCCCCC(=O)N[C@H]([C@H](O)\C=C\CCCCCCCCCCCCC)COC1OC(CO)C(O)C(O)C1O VJLLLMIZEJJZTE-VNQXHBPZSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000638510 Homo sapiens Acyl-coenzyme A thioesterase THEM4 Proteins 0.000 description 1
- 101001074618 Homo sapiens GPI mannosyltransferase 4 Proteins 0.000 description 1
- 101000887519 Homo sapiens Globoside alpha-1,3-N-acetylgalactosaminyltransferase 1 Proteins 0.000 description 1
- 101001133056 Homo sapiens Mucin-1 Proteins 0.000 description 1
- 101000904173 Homo sapiens Progonadoliberin-1 Proteins 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- 201000003803 Inflammatory myofibroblastic tumor Diseases 0.000 description 1
- 206010067917 Inflammatory myofibroblastic tumour Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 108010002386 Interleukin-3 Proteins 0.000 description 1
- 102100039064 Interleukin-3 Human genes 0.000 description 1
- 206010073365 Intraductal papillary mucinous carcinoma of pancreas Diseases 0.000 description 1
- 206010061252 Intraocular melanoma Diseases 0.000 description 1
- 208000009164 Islet Cell Adenoma Diseases 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- 102100040648 L-fucose kinase Human genes 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000002118 L01XE12 - Vandetanib Substances 0.000 description 1
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 1
- UIARLYUEJFELEN-LROUJFHJSA-N LSM-1231 Chemical compound C12=C3N4C5=CC=CC=C5C3=C3C(=O)NCC3=C2C2=CC=CC=C2N1[C@]1(C)[C@](CO)(O)C[C@H]4O1 UIARLYUEJFELEN-LROUJFHJSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 208000032004 Large-Cell Anaplastic Lymphoma Diseases 0.000 description 1
- 206010023825 Laryngeal cancer Diseases 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- JXLYSJRDGCGARV-PJXZDTQASA-N Leurosidine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-PJXZDTQASA-N 0.000 description 1
- LPGWZGMPDKDHEP-HLTPFJCJSA-N Leurosine Chemical compound C([C@]1([C@@H]2O1)CC)N(CCC=1C3=CC=CC=C3NC=11)C[C@H]2C[C@]1(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC LPGWZGMPDKDHEP-HLTPFJCJSA-N 0.000 description 1
- LPGWZGMPDKDHEP-GKWAKPNHSA-N Leurosine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@]6(CC)O[C@@H]6[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C LPGWZGMPDKDHEP-GKWAKPNHSA-N 0.000 description 1
- 206010025219 Lymphangioma Diseases 0.000 description 1
- 208000032271 Malignant tumor of penis Diseases 0.000 description 1
- 208000037196 Medullary thyroid carcinoma Diseases 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- HRHKSTOGXBBQCB-UHFFFAOYSA-N Mitomycin E Natural products O=C1C(N)=C(C)C(=O)C2=C1C(COC(N)=O)C1(OC)C3N(C)C3CN12 HRHKSTOGXBBQCB-UHFFFAOYSA-N 0.000 description 1
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 1
- 208000010190 Monoclonal Gammopathy of Undetermined Significance Diseases 0.000 description 1
- FNJSWIPFHMKRAT-UHFFFAOYSA-N Monomethyl phthalate Chemical compound COC(=O)C1=CC=CC=C1C(O)=O FNJSWIPFHMKRAT-UHFFFAOYSA-N 0.000 description 1
- 208000012799 Mu-heavy chain disease Diseases 0.000 description 1
- 102100034256 Mucin-1 Human genes 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- MSFSPUZXLOGKHJ-UHFFFAOYSA-N Muraminsaeure Natural products OC(=O)C(C)OC1C(N)C(O)OC(CO)C1O MSFSPUZXLOGKHJ-UHFFFAOYSA-N 0.000 description 1
- 206010028561 Myeloid metaplasia Diseases 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- FOFDIMHVKGYHRU-UHFFFAOYSA-N N-(1,3-benzodioxol-5-ylmethyl)-4-(4-benzofuro[3,2-d]pyrimidinyl)-1-piperazinecarbothioamide Chemical compound C12=CC=CC=C2OC2=C1N=CN=C2N(CC1)CCN1C(=S)NCC1=CC=C(OCO2)C2=C1 FOFDIMHVKGYHRU-UHFFFAOYSA-N 0.000 description 1
- 108010046220 N-Acetylgalactosaminyltransferases Proteins 0.000 description 1
- 102000007524 N-Acetylgalactosaminyltransferases Human genes 0.000 description 1
- VNBRGSXVFBYQNN-UHFFFAOYSA-N N-[4-[(2-amino-3-chloro-4-pyridinyl)oxy]-3-fluorophenyl]-4-ethoxy-1-(4-fluorophenyl)-2-oxo-3-pyridinecarboxamide Chemical compound O=C1C(C(=O)NC=2C=C(F)C(OC=3C(=C(N)N=CC=3)Cl)=CC=2)=C(OCC)C=CN1C1=CC=C(F)C=C1 VNBRGSXVFBYQNN-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-BKJPEWSUSA-N N-acetyl-D-hexosamine Chemical compound CC(=O)NC1C(O)O[C@H](CO)C(O)C1O OVRNDRQMDRJTHS-BKJPEWSUSA-N 0.000 description 1
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 1
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 description 1
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 description 1
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 208000009277 Neuroectodermal Tumors Diseases 0.000 description 1
- 208000003019 Neurofibromatosis 1 Diseases 0.000 description 1
- 101710138657 Neurotoxin Proteins 0.000 description 1
- 208000033755 Neutrophilic Chronic Leukemia Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 201000010133 Oligodendroglioma Diseases 0.000 description 1
- 206010031096 Oropharyngeal cancer Diseases 0.000 description 1
- 206010057444 Oropharyngeal neoplasm Diseases 0.000 description 1
- 101710160107 Outer membrane protein A Proteins 0.000 description 1
- 206010061328 Ovarian epithelial cancer Diseases 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 208000017459 Paget disease of the penis Diseases 0.000 description 1
- 208000025610 Paget disease of the vulva Diseases 0.000 description 1
- 206010033701 Papillary thyroid cancer Diseases 0.000 description 1
- 208000002471 Penile Neoplasms Diseases 0.000 description 1
- 206010034299 Penile cancer Diseases 0.000 description 1
- 108010057150 Peplomycin Proteins 0.000 description 1
- 108010013639 Peptidoglycan Proteins 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 208000009565 Pharyngeal Neoplasms Diseases 0.000 description 1
- 206010034811 Pharyngeal cancer Diseases 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 102000009097 Phosphorylases Human genes 0.000 description 1
- 108010073135 Phosphorylases Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 208000007641 Pinealoma Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 108010020346 Polyglutamic Acid Proteins 0.000 description 1
- 108010066816 Polypeptide N-acetylgalactosaminyltransferase Proteins 0.000 description 1
- 206010036524 Precursor B-lymphoblastic lymphomas Diseases 0.000 description 1
- 208000032758 Precursor T-lymphoblastic lymphoma/leukaemia Diseases 0.000 description 1
- 102100024028 Progonadoliberin-1 Human genes 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- 208000034541 Rare lymphatic malformation Diseases 0.000 description 1
- 235000009776 Rathbunia alamosensis Nutrition 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- BCZUAADEACICHN-UHFFFAOYSA-N SGX-523 Chemical compound C1=NN(C)C=C1C1=NN2C(SC=3C=C4C=CC=NC4=CC=3)=NN=C2C=C1 BCZUAADEACICHN-UHFFFAOYSA-N 0.000 description 1
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 description 1
- 206010061934 Salivary gland cancer Diseases 0.000 description 1
- 208000006938 Schwannomatosis Diseases 0.000 description 1
- 208000009359 Sezary Syndrome Diseases 0.000 description 1
- 208000021388 Sezary disease Diseases 0.000 description 1
- 229910004161 SiNa Inorganic materials 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 1
- 208000010502 Subcutaneous panniculitis-like T-cell lymphoma Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 101000996723 Sus scrofa Gonadotropin-releasing hormone receptor Proteins 0.000 description 1
- 201000008736 Systemic mastocytosis Diseases 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 1
- 208000029052 T-cell acute lymphoblastic leukemia Diseases 0.000 description 1
- 201000011648 T-cell childhood lymphoblastic lymphoma Diseases 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 208000020982 T-lymphoblastic lymphoma Diseases 0.000 description 1
- WFWLQNSHRPWKFK-UHFFFAOYSA-N Tegafur Chemical compound O=C1NC(=O)C(F)=CN1C1OCCC1 WFWLQNSHRPWKFK-UHFFFAOYSA-N 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- 206010043276 Teratoma Diseases 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- HATRDXDCPOXQJX-UHFFFAOYSA-N Thapsigargin Natural products CCCCCCCC(=O)OC1C(OC(O)C(=C/C)C)C(=C2C3OC(=O)C(C)(O)C3(O)C(CC(C)(OC(=O)C)C12)OC(=O)CCC)C HATRDXDCPOXQJX-UHFFFAOYSA-N 0.000 description 1
- 206010043515 Throat cancer Diseases 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 108010061048 UDPacetylglucosamine pyrophosphorylase Proteins 0.000 description 1
- LFTYTUAZOPRMMI-UHFFFAOYSA-N UNPD164450 Natural products O1C(CO)C(O)C(O)C(NC(=O)C)C1OP(O)(=O)OP(O)(=O)OCC1C(O)C(O)C(N2C(NC(=O)C=C2)=O)O1 LFTYTUAZOPRMMI-UHFFFAOYSA-N 0.000 description 1
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical class O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 1
- 206010046431 Urethral cancer Diseases 0.000 description 1
- 206010046458 Urethral neoplasms Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 201000005969 Uveal melanoma Diseases 0.000 description 1
- 208000014070 Vestibular schwannoma Diseases 0.000 description 1
- 206010047741 Vulval cancer Diseases 0.000 description 1
- 208000004354 Vulvar Neoplasms Diseases 0.000 description 1
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- NBLHOLNNKJBEDC-XOGQCRKLSA-N [(2r,3s,4s,5r,6r)-2-[(2r,3s,4s,5s,6s)-2-[(1r,2s)-2-[[6-amino-2-[(1s)-3-amino-1-[[(2s)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-3-[[(2r,3s,4s)-5-[[(2s,3r)-1-[2-[4-[4-[4-(diaminomethylideneamino)butylcarbamoyl]-1,3-th Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCCCN=C(N)N)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C NBLHOLNNKJBEDC-XOGQCRKLSA-N 0.000 description 1
- DULZJSBFYXKCJG-UHFFFAOYSA-M [OH-].[Si+4].CN(C)CCC[Si](C)(C)[O-].c1ccc2c3nc(nc4[n-]c(nc5nc(nc6[n-]c(n3)c3ccccc63)c3ccccc53)c3ccccc43)c2c1 Chemical compound [OH-].[Si+4].CN(C)CCC[Si](C)(C)[O-].c1ccc2c3nc(nc4[n-]c(nc5nc(nc6[n-]c(n3)c3ccccc63)c3ccccc53)c3ccccc43)c2c1 DULZJSBFYXKCJG-UHFFFAOYSA-M 0.000 description 1
- 229940028652 abraxane Drugs 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- JXLYSJRDGCGARV-KSNABSRWSA-N ac1l29ym Chemical compound C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-KSNABSRWSA-N 0.000 description 1
- 229940022663 acetate Drugs 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 208000004064 acoustic neuroma Diseases 0.000 description 1
- 229930183665 actinomycin Natural products 0.000 description 1
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000005585 adamantoate group Chemical group 0.000 description 1
- 201000005188 adrenal gland cancer Diseases 0.000 description 1
- 208000024447 adrenal gland neoplasm Diseases 0.000 description 1
- 229940042992 afinitor Drugs 0.000 description 1
- 229960000548 alemtuzumab Drugs 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000004450 alkenylene group Chemical group 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 125000004419 alkynylene group Chemical group 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- 229940037003 alum Drugs 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229960003896 aminopterin Drugs 0.000 description 1
- APUPEJJSWDHEBO-UHFFFAOYSA-P ammonium molybdate Chemical compound [NH4+].[NH4+].[O-][Mo]([O-])(=O)=O APUPEJJSWDHEBO-UHFFFAOYSA-P 0.000 description 1
- 239000011609 ammonium molybdate Substances 0.000 description 1
- 235000018660 ammonium molybdate Nutrition 0.000 description 1
- 229940010552 ammonium molybdate Drugs 0.000 description 1
- 206010002022 amyloidosis Diseases 0.000 description 1
- 238000012863 analytical testing Methods 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 206010002449 angioimmunoblastic T-cell lymphoma Diseases 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 230000005875 antibody response Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 210000000612 antigen-presenting cell Anatomy 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 201000011165 anus cancer Diseases 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000000732 arylene group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 229960003272 asparaginase Drugs 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- KVPFKMBYCSISTN-UHFFFAOYSA-N benzylsulfanylformic acid Chemical compound OC(=O)SCC1=CC=CC=C1 KVPFKMBYCSISTN-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N beta-phenylpropanoic acid Natural products OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 1
- 201000009036 biliary tract cancer Diseases 0.000 description 1
- 208000020790 biliary tract neoplasm Diseases 0.000 description 1
- UXXXZMDJQLPQPH-UHFFFAOYSA-N bis(2-methylpropyl) carbonate Chemical compound CC(C)COC(=O)OCC(C)C UXXXZMDJQLPQPH-UHFFFAOYSA-N 0.000 description 1
- ACBQROXDOHKANW-UHFFFAOYSA-N bis(4-nitrophenyl) carbonate Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC(=O)OC1=CC=C([N+]([O-])=O)C=C1 ACBQROXDOHKANW-UHFFFAOYSA-N 0.000 description 1
- JKJWYKGYGWOAHT-UHFFFAOYSA-N bis(prop-2-enyl) carbonate Chemical compound C=CCOC(=O)OCC=C JKJWYKGYGWOAHT-UHFFFAOYSA-N 0.000 description 1
- PNQFSBOTHXRUJW-UHFFFAOYSA-N bis[2-(benzenesulfonyl)ethyl] carbonate Chemical compound C=1C=CC=CC=1S(=O)(=O)CCOC(=O)OCCS(=O)(=O)C1=CC=CC=C1 PNQFSBOTHXRUJW-UHFFFAOYSA-N 0.000 description 1
- NBLHOLNNKJBEDC-UHFFFAOYSA-N bleomycin B2 Natural products N=1C(C=2SC=C(N=2)C(=O)NCCCCN=C(N)N)=CSC=1CCNC(=O)C(C(O)C)NC(=O)C(C)C(O)C(C)NC(=O)C(C(OC1C(C(O)C(O)C(CO)O1)OC1C(C(OC(N)=O)C(O)C(CO)O1)O)C=1NC=NC=1)NC(=O)C1=NC(C(CC(N)=O)NCC(N)C(N)=O)=NC(N)=C1C NBLHOLNNKJBEDC-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 1
- UBPYILGKFZZVDX-UHFFFAOYSA-N bosutinib Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 description 1
- 201000008274 breast adenocarcinoma Diseases 0.000 description 1
- 201000000135 breast papillary carcinoma Diseases 0.000 description 1
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 1
- 201000005200 bronchus cancer Diseases 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229940112129 campath Drugs 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 230000005880 cancer cell killing Effects 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- DKVNPHBNOWQYFE-UHFFFAOYSA-N carbamodithioic acid Chemical compound NC(S)=S DKVNPHBNOWQYFE-UHFFFAOYSA-N 0.000 description 1
- WUMKXNDWLUNXEO-UHFFFAOYSA-N carbamothioic S-acid sulfane Chemical group S.NC(S)=O.NC(S)=O WUMKXNDWLUNXEO-UHFFFAOYSA-N 0.000 description 1
- 125000004452 carbocyclyl group Chemical group 0.000 description 1
- 150000001722 carbon compounds Chemical class 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000005859 cell recognition Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- AEULIVPVIDOLIN-UHFFFAOYSA-N cep-11981 Chemical compound C1=C2C3=C4CNC(=O)C4=C4C5=CN(C)N=C5CCC4=C3N(CC(C)C)C2=CC=C1NC1=NC=CC=N1 AEULIVPVIDOLIN-UHFFFAOYSA-N 0.000 description 1
- 229940106189 ceramide Drugs 0.000 description 1
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 description 1
- 201000006662 cervical adenocarcinoma Diseases 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 1
- GBVKRUOMSUTVPW-AHNVSIPUSA-N chembl1089636 Chemical compound N([C@H]([C@@H](OC(=O)CCC(=O)N[C@@H](C(O)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)NCC(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCCNC(=O)CCC(=O)O[C@H]([C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)C(=O)O[C@@H]1C(=C2[C@@H](OC(C)=O)C(=O)[C@]3(C)[C@@H](O)C[C@H]4OC[C@]4([C@H]3[C@H](OC(=O)C=3C=CC=CC=3)[C@](C2(C)C)(O)C1)OC(C)=O)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCCNC(=O)CCC(=O)O[C@H]([C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)C(=O)O[C@@H]1C(=C2[C@@H](OC(C)=O)C(=O)[C@]3(C)[C@@H](O)C[C@H]4OC[C@]4([C@H]3[C@H](OC(=O)C=3C=CC=CC=3)[C@](C2(C)C)(O)C1)OC(C)=O)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)C(=O)O[C@@H]1C(=C2[C@@H](OC(C)=O)C(=O)[C@]3(C)[C@@H](O)C[C@H]4OC[C@]4([C@H]3[C@H](OC(=O)C=3C=CC=CC=3)[C@](C2(C)C)(O)C1)OC(C)=O)C)C=1C=CC=CC=1)C(=O)C1=CC=CC=C1 GBVKRUOMSUTVPW-AHNVSIPUSA-N 0.000 description 1
- JXDYOSVKVSQGJM-UHFFFAOYSA-N chembl3109738 Chemical compound N1C2=CC(Br)=CC=C2CN(C)CCCCCOC2=CC3=C1N=CN=C3C=C2OC JXDYOSVKVSQGJM-UHFFFAOYSA-N 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229940089960 chloroacetate Drugs 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-M chloroacetate Chemical compound [O-]C(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-M 0.000 description 1
- SBPBAQFWLVIOKP-UHFFFAOYSA-N chlorpyrifos Chemical compound CCOP(=S)(OCC)OC1=NC(Cl)=C(Cl)C=C1Cl SBPBAQFWLVIOKP-UHFFFAOYSA-N 0.000 description 1
- HPNSNYBUADCFDR-UHFFFAOYSA-N chromafenozide Chemical compound CC1=CC(C)=CC(C(=O)N(NC(=O)C=2C(=C3CCCOC3=CC=2)C)C(C)(C)C)=C1 HPNSNYBUADCFDR-UHFFFAOYSA-N 0.000 description 1
- 201000010903 chronic neutrophilic leukemia Diseases 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 239000000571 coke Substances 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 230000004540 complement-dependent cytotoxicity Effects 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000001268 conjugating effect Effects 0.000 description 1
- 229960005061 crizotinib Drugs 0.000 description 1
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 208000002445 cystadenocarcinoma Diseases 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical class NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- LVXJQMNHJWSHET-AATRIKPKSA-N dacomitinib Chemical compound C=12C=C(NC(=O)\C=C\CN3CCCCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 LVXJQMNHJWSHET-AATRIKPKSA-N 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 229950006418 dactolisib Drugs 0.000 description 1
- JOGKUKXHTYWRGZ-UHFFFAOYSA-N dactolisib Chemical compound O=C1N(C)C2=CN=C3C=CC(C=4C=C5C=CC=CC5=NC=4)=CC3=C2N1C1=CC=C(C(C)(C)C#N)C=C1 JOGKUKXHTYWRGZ-UHFFFAOYSA-N 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 229960000958 deferoxamine Drugs 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- PIZLBWGMERQCOC-UHFFFAOYSA-N dibenzyl carbonate Chemical compound C=1C=CC=CC=1COC(=O)OCC1=CC=CC=C1 PIZLBWGMERQCOC-UHFFFAOYSA-N 0.000 description 1
- 229940120124 dichloroacetate Drugs 0.000 description 1
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 108020001096 dihydrofolate reductase Proteins 0.000 description 1
- 239000003166 dihydrofolate reductase inhibitor Substances 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 150000002016 disaccharides Chemical group 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000012990 dithiocarbamate Substances 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 229950005454 doxifluridine Drugs 0.000 description 1
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- FSIRXIHZBIXHKT-MHTVFEQDSA-N edatrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CC(CC)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FSIRXIHZBIXHKT-MHTVFEQDSA-N 0.000 description 1
- 229950006700 edatrexate Drugs 0.000 description 1
- 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 1
- 201000011025 embryonal testis carcinoma Diseases 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- HKSZLNNOFSGOKW-UHFFFAOYSA-N ent-staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 HKSZLNNOFSGOKW-UHFFFAOYSA-N 0.000 description 1
- 210000003979 eosinophil Anatomy 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 208000037828 epithelial carcinoma Diseases 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- 208000028653 esophageal adenocarcinoma Diseases 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- LIQODXNTTZAGID-OCBXBXKTSA-N etoposide phosphate Chemical compound COC1=C(OP(O)(O)=O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 LIQODXNTTZAGID-OCBXBXKTSA-N 0.000 description 1
- 229960000752 etoposide phosphate Drugs 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 208000024519 eye neoplasm Diseases 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- FGIVSGPRGVABAB-UHFFFAOYSA-N fluoren-9-ylmethyl hydrogen carbonate Chemical compound C1=CC=C2C(COC(=O)O)C3=CC=CC=C3C2=C1 FGIVSGPRGVABAB-UHFFFAOYSA-N 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 1
- 235000008191 folinic acid Nutrition 0.000 description 1
- 239000011672 folinic acid Substances 0.000 description 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 108010083136 fucokinase Proteins 0.000 description 1
- 208000024386 fungal infectious disease Diseases 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 201000010175 gallbladder cancer Diseases 0.000 description 1
- 229920000370 gamma-poly(glutamate) polymer Polymers 0.000 description 1
- 201000006585 gastric adenocarcinoma Diseases 0.000 description 1
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 229940080856 gleevec Drugs 0.000 description 1
- 229950007540 glesatinib Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000002339 glycosphingolipids Chemical class 0.000 description 1
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical compound C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 201000002222 hemangioblastoma Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 125000005549 heteroarylene group Chemical group 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 229960001507 ibrutinib Drugs 0.000 description 1
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 125000000879 imine group Chemical group 0.000 description 1
- 210000001822 immobilized cell Anatomy 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000003832 immune regulation Effects 0.000 description 1
- 230000006058 immune tolerance Effects 0.000 description 1
- 230000001571 immunoadjuvant effect Effects 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 230000000984 immunochemical effect Effects 0.000 description 1
- 229940127121 immunoconjugate Drugs 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 231100000405 induce cancer Toxicity 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 201000002313 intestinal cancer Diseases 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229940084651 iressa Drugs 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 201000002529 islet cell tumor Diseases 0.000 description 1
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 208000022013 kidney Wilms tumor Diseases 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 206010023841 laryngeal neoplasm Diseases 0.000 description 1
- 229960004942 lenalidomide Drugs 0.000 description 1
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 1
- 229960001691 leucovorin Drugs 0.000 description 1
- 230000021633 leukocyte mediated immunity Effects 0.000 description 1
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 1
- 229960004338 leuprorelin Drugs 0.000 description 1
- 229940058352 levulinate Drugs 0.000 description 1
- MPVGZUGXCQEXTM-UHFFFAOYSA-N linifanib Chemical compound CC1=CC=C(F)C(NC(=O)NC=2C=CC(=CC=2)C=2C=3C(N)=NNC=3C=CC=2)=C1 MPVGZUGXCQEXTM-UHFFFAOYSA-N 0.000 description 1
- 229920006008 lipopolysaccharide Polymers 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- 229940076783 lucentis Drugs 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 229960005375 lutein Drugs 0.000 description 1
- 235000012680 lutein Nutrition 0.000 description 1
- KBPHJBAIARWVSC-RGZFRNHPSA-N lutein Chemical compound C([C@H](O)CC=1C)C(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\[C@H]1C(C)=C[C@H](O)CC1(C)C KBPHJBAIARWVSC-RGZFRNHPSA-N 0.000 description 1
- 239000001656 lutein Substances 0.000 description 1
- ORAKUVXRZWMARG-WZLJTJAWSA-N lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C ORAKUVXRZWMARG-WZLJTJAWSA-N 0.000 description 1
- 208000037829 lymphangioendotheliosarcoma Diseases 0.000 description 1
- 208000012804 lymphangiosarcoma Diseases 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 201000007919 lymphoplasmacytic lymphoma Diseases 0.000 description 1
- 229940124302 mTOR inhibitor Drugs 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 201000007924 marginal zone B-cell lymphoma Diseases 0.000 description 1
- 208000021937 marginal zone lymphoma Diseases 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 208000008585 mastocytosis Diseases 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 208000030163 medullary breast carcinoma Diseases 0.000 description 1
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 description 1
- 229960001786 megestrol Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 206010027191 meningioma Diseases 0.000 description 1
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- RMIODHQZRUFFFF-UHFFFAOYSA-M methoxyacetate Chemical compound COCC([O-])=O RMIODHQZRUFFFF-UHFFFAOYSA-M 0.000 description 1
- CPMDPSXJELVGJG-UHFFFAOYSA-N methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate Chemical compound OC=1NC2=CC(=CC=C2C=1C(=NC1=CC=C(C=C1)N(C(CN1CCN(CC1)C)=O)C)C1=CC=CC=C1)C(=O)OC CPMDPSXJELVGJG-UHFFFAOYSA-N 0.000 description 1
- CXHHBNMLPJOKQD-UHFFFAOYSA-M methyl carbonate Chemical compound COC([O-])=O CXHHBNMLPJOKQD-UHFFFAOYSA-M 0.000 description 1
- HRHKSTOGXBBQCB-VFWICMBZSA-N methylmitomycin Chemical compound O=C1C(N)=C(C)C(=O)C2=C1[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N(C)[C@H]3CN12 HRHKSTOGXBBQCB-VFWICMBZSA-N 0.000 description 1
- NYEBKUUITGFJAK-UHFFFAOYSA-N methylsulfanylmethanethioic s-acid Chemical compound CSC(O)=S NYEBKUUITGFJAK-UHFFFAOYSA-N 0.000 description 1
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 1
- 244000000010 microbial pathogen Species 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 201000005328 monoclonal gammopathy of uncertain significance Diseases 0.000 description 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 208000026114 mu chain disease Diseases 0.000 description 1
- 208000022669 mucinous neoplasm Diseases 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
- 230000001400 myeloablative effect Effects 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 208000001611 myxosarcoma Diseases 0.000 description 1
- CLVOYFRAZKMSPF-UHFFFAOYSA-N n,n-dibutyl-4-chlorobenzenesulfonamide Chemical compound CCCCN(CCCC)S(=O)(=O)C1=CC=C(Cl)C=C1 CLVOYFRAZKMSPF-UHFFFAOYSA-N 0.000 description 1
- DDOVBCWVTOHGCU-QMXMISKISA-N n-[(e,2s,3r)-3-hydroxy-1-[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxynonadec-4-en-2-yl]octadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(=O)N[C@H]([C@H](O)\C=C\CCCCCCCCCCCCCC)CO[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O DDOVBCWVTOHGCU-QMXMISKISA-N 0.000 description 1
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 description 1
- YRCHYHRCBXNYNU-UHFFFAOYSA-N n-[[3-fluoro-4-[2-[5-[(2-methoxyethylamino)methyl]pyridin-2-yl]thieno[3,2-b]pyridin-7-yl]oxyphenyl]carbamothioyl]-2-(4-fluorophenyl)acetamide Chemical compound N1=CC(CNCCOC)=CC=C1C1=CC2=NC=CC(OC=3C(=CC(NC(=S)NC(=O)CC=4C=CC(F)=CC=4)=CC=3)F)=C2S1 YRCHYHRCBXNYNU-UHFFFAOYSA-N 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- LNIQEBQSPWOLPH-UHFFFAOYSA-N naphthalene-1-carboxylic acid Chemical compound OC(=O)c1cccc2ccccc12.OC(=O)c1cccc2ccccc12 LNIQEBQSPWOLPH-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 201000008026 nephroblastoma Diseases 0.000 description 1
- JWNPDZNEKVCWMY-VQHVLOKHSA-N neratinib Chemical compound C=12C=C(NC(=O)\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 JWNPDZNEKVCWMY-VQHVLOKHSA-N 0.000 description 1
- 201000009494 neurilemmomatosis Diseases 0.000 description 1
- 208000002761 neurofibromatosis 2 Diseases 0.000 description 1
- 208000022032 neurofibromatosis type 2 Diseases 0.000 description 1
- 239000002581 neurotoxin Substances 0.000 description 1
- 231100000618 neurotoxin Toxicity 0.000 description 1
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 1
- 229940080607 nexavar Drugs 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229960000435 oblimersen Drugs 0.000 description 1
- MIMNFCVQODTQDP-NDLVEFNKSA-N oblimersen Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(S)(=O)O[C@@H]2[C@H](O[C@H](C2)N2C3=NC=NC(N)=C3N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=C(C(NC(N)=N3)=O)N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C3=NC=NC(N)=C3N=C2)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(N=C(N)C=C2)=O)COP(O)(=S)O[C@@H]2[C@H](O[C@H](C2)N2C(NC(=O)C(C)=C2)=O)CO)[C@@H](O)C1 MIMNFCVQODTQDP-NDLVEFNKSA-N 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 125000005069 octynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 description 1
- 201000008106 ocular cancer Diseases 0.000 description 1
- 201000002575 ocular melanoma Diseases 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 201000006958 oropharynx cancer Diseases 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 208000013371 ovarian adenocarcinoma Diseases 0.000 description 1
- 201000011029 ovarian embryonal carcinoma Diseases 0.000 description 1
- 201000006588 ovary adenocarcinoma Diseases 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 125000006505 p-cyanobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C#N)C([H])([H])* 0.000 description 1
- 229960002239 paclitaxel poliglumex Drugs 0.000 description 1
- 108010046239 paclitaxel-Angiopep-2 conjugate Proteins 0.000 description 1
- 229940090244 palladia Drugs 0.000 description 1
- 201000004754 pancreatic intraductal papillary-mucinous neoplasm Diseases 0.000 description 1
- 208000022102 pancreatic neuroendocrine neoplasm Diseases 0.000 description 1
- 208000004019 papillary adenocarcinoma Diseases 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229940046159 pegylated liposomal doxorubicin Drugs 0.000 description 1
- 229960005079 pemetrexed Drugs 0.000 description 1
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 229940100684 pentylamine Drugs 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- QIMGFXOHTOXMQP-GFAGFCTOSA-N peplomycin Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCCN[C@@H](C)C=1C=CC=CC=1)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C QIMGFXOHTOXMQP-GFAGFCTOSA-N 0.000 description 1
- 229950003180 peplomycin Drugs 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- PWXJULSLLONQHY-UHFFFAOYSA-N phenylcarbamic acid Chemical compound OC(=O)NC1=CC=CC=C1 PWXJULSLLONQHY-UHFFFAOYSA-N 0.000 description 1
- FAQJJMHZNSSFSM-UHFFFAOYSA-N phenylglyoxylic acid Chemical compound OC(=O)C(=O)C1=CC=CC=C1 FAQJJMHZNSSFSM-UHFFFAOYSA-N 0.000 description 1
- NIXKBAZVOQAHGC-UHFFFAOYSA-N phenylmethanesulfonic acid Chemical compound OS(=O)(=O)CC1=CC=CC=C1 NIXKBAZVOQAHGC-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- IEQIEDJGQAUEQZ-UHFFFAOYSA-N phthalocyanine Chemical compound N1C(N=C2C3=CC=CC=C3C(N=C3C4=CC=CC=C4C(=N4)N3)=N2)=C(C=CC=C2)C2=C1N=C1C2=CC=CC=C2C4=N1 IEQIEDJGQAUEQZ-UHFFFAOYSA-N 0.000 description 1
- 208000024724 pineal body neoplasm Diseases 0.000 description 1
- 201000004123 pineal gland cancer Diseases 0.000 description 1
- 125000005547 pivalate group Chemical group 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- PHXJVRSECIGDHY-UHFFFAOYSA-N ponatinib Chemical compound C1CN(C)CCN1CC(C(=C1)C(F)(F)F)=CC=C1NC(=O)C1=CC=C(C)C(C#CC=2N3N=CC=CC3=NC=2)=C1 PHXJVRSECIGDHY-UHFFFAOYSA-N 0.000 description 1
- 229960001131 ponatinib Drugs 0.000 description 1
- 229950004406 porfiromycin Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- 201000006037 primary mediastinal B-cell lymphoma Diseases 0.000 description 1
- 208000029340 primitive neuroectodermal tumor Diseases 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 description 1
- 201000005825 prostate adenocarcinoma Diseases 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 229940121649 protein inhibitor Drugs 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229940030966 pyrrole Drugs 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- CVWXJKQAOSCOAB-UHFFFAOYSA-N quizartinib Chemical compound O1C(C(C)(C)C)=CC(NC(=O)NC=2C=CC(=CC=2)C=2N=C3N(C4=CC=C(OCCN5CCOCC5)C=C4S3)C=2)=N1 CVWXJKQAOSCOAB-UHFFFAOYSA-N 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229960003876 ranibizumab Drugs 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 201000006845 reticulosarcoma Diseases 0.000 description 1
- 208000029922 reticulum cell sarcoma Diseases 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 210000004706 scrotum Anatomy 0.000 description 1
- 208000014956 scrotum Paget disease Diseases 0.000 description 1
- 201000008407 sebaceous adenocarcinoma Diseases 0.000 description 1
- 229950008834 seribantumab Drugs 0.000 description 1
- 238000002333 serotherapy Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- PCMORTLOPMLEFB-ONEGZZNKSA-N sinapic acid Chemical compound COC1=CC(\C=C\C(O)=O)=CC(OC)=C1O PCMORTLOPMLEFB-ONEGZZNKSA-N 0.000 description 1
- PCMORTLOPMLEFB-UHFFFAOYSA-N sinapinic acid Natural products COC1=CC(C=CC(O)=O)=CC(OC)=C1O PCMORTLOPMLEFB-UHFFFAOYSA-N 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 206010062113 splenic marginal zone lymphoma Diseases 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 1
- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940034785 sutent Drugs 0.000 description 1
- 210000000106 sweat gland Anatomy 0.000 description 1
- 201000010965 sweat gland carcinoma Diseases 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 229940120982 tarceva Drugs 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- XKXIQBVKMABYQJ-UHFFFAOYSA-M tert-butyl carbonate Chemical compound CC(C)(C)OC([O-])=O XKXIQBVKMABYQJ-UHFFFAOYSA-M 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229950003046 tesevatinib Drugs 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 206010062123 testicular embryonal carcinoma Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- IXFPJGBNCFXKPI-FSIHEZPISA-N thapsigargin Chemical compound CCCC(=O)O[C@H]1C[C@](C)(OC(C)=O)[C@H]2[C@H](OC(=O)CCCCCCC)[C@@H](OC(=O)C(\C)=C/C)C(C)=C2[C@@H]2OC(=O)[C@@](C)(O)[C@]21O IXFPJGBNCFXKPI-FSIHEZPISA-N 0.000 description 1
- 229940021747 therapeutic vaccine Drugs 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 208000013818 thyroid gland medullary carcinoma Diseases 0.000 description 1
- 238000001269 time-of-flight mass spectrometry Methods 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- 229960005048 toceranib Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229940100411 torisel Drugs 0.000 description 1
- KBPHJBAIARWVSC-XQIHNALSSA-N trans-lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C KBPHJBAIARWVSC-XQIHNALSSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 229960001612 trastuzumab emtansine Drugs 0.000 description 1
- AYNNSCRYTDRFCP-UHFFFAOYSA-N triazene Chemical compound NN=N AYNNSCRYTDRFCP-UHFFFAOYSA-N 0.000 description 1
- 229940066528 trichloroacetate Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 229940094060 tykerb Drugs 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
- 208000037965 uterine sarcoma Diseases 0.000 description 1
- 206010046885 vaginal cancer Diseases 0.000 description 1
- 208000013139 vaginal neoplasm Diseases 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- ABDKAPXRBAPSQN-UHFFFAOYSA-N veratrole Chemical compound COC1=CC=CC=C1OC ABDKAPXRBAPSQN-UHFFFAOYSA-N 0.000 description 1
- ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N verteporfin Chemical compound C=1C([C@@]2([C@H](C(=O)OC)C(=CC=C22)C(=O)OC)C)=NC2=CC(C(=C2C=C)C)=NC2=CC(C(=C2CCC(O)=O)C)=NC2=CC2=NC=1C(C)=C2CCC(=O)OC ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N 0.000 description 1
- 229960003895 verteporfin Drugs 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical class C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 201000005102 vulva cancer Diseases 0.000 description 1
- 208000028010 vulval Paget disease Diseases 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- FJHBOVDFOQMZRV-XQIHNALSSA-N xanthophyll Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C=C(C)C(O)CC2(C)C FJHBOVDFOQMZRV-XQIHNALSSA-N 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
- A61K47/646—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent the entire peptide or protein drug conjugate elicits an immune response, e.g. conjugate vaccines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
- A61K39/0011—Cancer antigens
- A61K39/001169—Tumor associated carbohydrates
- A61K39/001173—Globo-H
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0016—Combination vaccines based on diphtheria-tetanus-pertussis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
- A61K47/6415—Toxins or lectins, e.g. clostridial toxins or Pseudomonas exotoxins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- C07K14/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Clostridium (G)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- C07K14/34—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Corynebacterium (G)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
- A61K2039/6031—Proteins
- A61K2039/6037—Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
- C07H3/06—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
- G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
- G01N2333/4701—Details
- G01N2333/4728—Details alpha-Glycoproteins
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Organic Chemistry (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Virology (AREA)
- Biochemistry (AREA)
- Oncology (AREA)
- Toxicology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Inorganic Chemistry (AREA)
- Materials Engineering (AREA)
- Polymers & Plastics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Peptides Or Proteins (AREA)
Description
本發明是有關於一種新穎之聚醣共軛物及其用途。
腫瘤相關醣類抗原(Tumor associated carbohydrate antigen, TACA)會過量表現於癌細胞表面,且與腫瘤細胞的附著及轉移相關。因此,許多癌症疫苗即是針對TACA進行設計研發。基於多數TACA並無法有效誘發免疫反應,目前已發展出數種方法來增加醣類疫苗的免疫性,包含與載體蛋白結合、與免疫佐劑一同施用、使用非天然的醣苷鍵(glycosidic linkage)、聚集抗原、單分子多價疫苗及異-聚醣多價疫苗。利用該些方法已設計出幾種對標的聚醣結構能產生顯著免疫反應的醣類疫苗,用以治療癌症並進入人體臨床測試。在該些醣類疫苗中,Theratope及GMK加上佐劑QS-21的臨床試驗已證實其對時間-疾病(time-to-disease)與整體存活率之間沒有顯著差異。推測原因可能是由於該些疫苗無法引發病患產生大量與T細胞相關的免疫反應。具體來說,Theratope及GMK雖可引發病患產生高量的IgM,卻無法使其產生強烈的免疫IgG反應;無法有效提升IgG免疫反應乃係研發醣類疫苗亟需克服的難題之一。
Globo H (GH; Fucα1→2Galβ1→3GalNacβ1→3Galα1→4Galβ1→4Glc)是Globo系列鞘糖脂(glycosphingolipid)的成員之一。1983年首次發現會過量表現於人類畸胎瘤細胞及乳癌MCF-7細胞;之後亦陸續被證實會於乳癌、前列腺癌、卵巢癌、胰臟癌、腦癌、子宮內膜癌、胃癌、大腸直腸癌及肺癌等癌細胞上過量表現。利用KLH作為載體,並以QS-21作為佐劑而由Livingston及Danishefsky兩人製成的Globo H疫苗,在臨床試驗第I期已證實可治療轉移性乳癌病患。經改善其合成方式後,目前該疫苗已在台灣進行晚期乳癌病患的第III期臨床試驗,並於美國、韓國、香港及印度進行晚期乳癌病患的第II期臨床試驗;以及在台灣進行卵巢癌病患的第II期臨床試驗。然而,早期的臨床試驗結果指出,疫苗誘發出IgM抗體的含量仍會高於IgG抗體的含量。近期,發明人利用白喉類毒素交互反應物質197 (diphtheria toxoid cross-reactive material (CRM) 197 (DT))作為載體,並以醣脂C34作為佐劑,研發出一較佳的疫苗,該疫苗可誘發抗體類型轉換(class switch)以產生大量可對抗GH、GH之片段Gb5及SSEA4的IgG抗體,上述GH、GH之片段Gb5及SSEA4均會表現於乳癌細胞及癌症幹細胞上。
相關研究已證實修飾醣類抗原結構(modification of carbohydrate antigen structure, MCAS)可有效提升免疫反應。舉例來說,在改造B型腦膜炎球菌的莢膜多醣時,將α-(2,8)-連接之聚唾液酸(α-(2,8)-linked polysialic acid, PSA)的N
-乙醯基置換為N
-丙醯基可誘發高量抗體反應,以辨識N
-丙醯基PSA,以及天然的N
-乙醯基 PSA。相似的修飾方法亦可應用於STn及GM3抗體,據以產生可同時辨識修飾及天然形式之抗原的高效價抗體。該些結果指出,修飾聚醣抗原之N
-苯乙醯基、N3
、N
-氟乙醯基或N
-雙氟乙醯基可改善其免疫誘發能力。此外,Schultz等人則指出,將對硝基苯基丙胺酸(p
-nitrophenylalanine)嵌入腫瘤壞死因子(tumor necrosis factor-α, TNF-α)可破壞免疫耐受性,並引發對TNF-α的抗體反應。目前雖已有多項研發是利用聚醣作為抗原,然主要仍是以修飾N端雙醣(STn)、三醣(GM3)及聚唾液酸(PSA)方式為主,其餘則是利用氟化MUC1醣肽抗原來進行製備。相關領域缺乏一整體策略來製備醣類疫苗,據以引發長效型IgG反應。
本發明是關於利用本揭示內容所述之特定化學基團來修飾Globo H的還原端葡萄糖或是非還原端海藻糖(fucose),可引發可專一辨識Globo H (GH)、Gb5及SSEA4之大量的IgG抗體反應。由包含此非天然聚醣結構之免疫組合物所引發的抗體可辨識會表現GH的腫瘤細胞(MCF-7),並產生與補體相關之細胞毒殺反應來對抗腫瘤細胞。
據此,本發明是關於合成型聚醣共軛物、包含該合成型聚醣共軛物的免疫組合物及疫苗。本發明亦是關於利用合成型聚醣共軛物及其免疫組合物來治療癌症或降低個體罹患癌症之風險的方法。
在一態樣中,本發明是關於式(I)之化合物,或其鹽類, 其中, X1
是-OR或-SR,其中R是氫、或是氧或硫之保護基、可任選取代的C1-10
烷基、可任選取代的芳香基、可任選取代的醯基或可任選取代的亞胺基(imidoyl); R1
及R2
係分別選自由氫、鹵素、可任選取代的烷基、可任選取代的烯基、可任選取代的炔基、可任選取代的雜環基、可任選取代的芳香基、-N3
、-NO2
、-N(RB
)2
、-N(RA
)C(O)RA
、-ORA
、-OC(O)RA
、-SRA
、-C(O)N(RB
)2
、-CN、-C(O)RA
、-C(O)ORA
、-S(O)RA
、-SO2
RA
、-SO2
N(RB
)2
及-NHSO2
RB
所組成群組; RA
係選自由氫、可任選取代的烷基、可任選取代的烯基、可任選取代的炔基、可任選取代的雜環基、可任選取代的芳香基所組成的群組; RB
係選自由氫、可任選取代的烷基、可任選取代的烯基、可任選取代的炔基、可任選取代的雜環基、可任選取代的芳香基所組成的群組;以及 若R1
是-OH,則R2
不是-CH3
;若R2
是-CH3
,則R1
不是-OH。
在另一態樣中,本發明是關於一種免疫組合物,包含(a)一聚醣共軛物,其係包含至少一種與連結子(linker)結合的聚醣及載體(carrier),其中該至少一種聚醣是藉由該連結子而與該載體形成共軛;以及(b)一非必要性之佐劑,其中該至少一種與連結子結合的聚醣具有式(II)之化學結構:其中, R1
及R2
係分別選自由氫、鹵素、可任選取代的烷基、可任選取代的烯基、可任選取代的炔基、可任選取代的雜環基、可任選取代的芳香基、-N3
、-NO2
、-N(RB
)2
、-N(RA
)C(O)RA
、-ORA
、-OC(O)RA
、-SRA
、-C(O)N(RB
)2
、-CN、-C(O)RA
、-C(O)ORA
、-S(O)RA
、-SO2
RA
、-SO2
N(RB
)2
及-NHSO2
RB
所組成的群組; RA
係選自由氫、可任選取代的烷基、可任選取代的烯基、可任選取代的炔基、可任選取代的雜環基、可任選取代的芳香基所組成的群組; RB
係選自由氫、可任選取代的烷基、可任選取代的烯基、可任選取代的炔基、可任選取代的雜環基、可任選取代的芳香基所組成的群組;以及 若R1
是-OH,則R2
不是-CH3
;若R2
是-CH3
,則R1
不是-OH。
或者是,該至少一種與連結子結合之聚醣具有式(IV)之化學結構:式(IV) 其中,R1
、R2
、RA
及RB
分別如式(II)之定義;若R1
是-OH,則R2
不是-CH3
;若R2
是-CH3
,則R1
不是-OH。
在本發明一實施方式中,R1
是-OH、-F、-N3
、-NO2
或芳氧基。
在另一實施方式中,R2
是-CH3
、-CH2
F、-CH2
N3
、-CH2
NO2
、-CH2
OH或炔基。
在另一實施方式中,R1
是-F、-N3
、-NO2
、或,且R2
是-CH3
。
在另一實施方式中,R1
是-OH,且R2
是-CH2
F、-CH2
N3
、-CH2
NO2
、-CH2
OH或-C≡CH。
「n」一詞在本說明書是指介於1到10的正整數。因此,n可以是1、2、3、4、5、6、7、8、9或10。
在另一實施方式中,連結子是一是異-(hetero-)或同-(homo-)雙功能連結子(bifunctional linker)。
在另一實施方式中,連結子是,其中L1
是一鍵結、-O-、-S-、-NRL1a
-、-C(=O)-、-NRL1a
C(=O)-、-NRL1a
C(=O)O-、-C(=O)NRL1a
-、-OC(=O)NRL1a
-、 -SC(=O)-、-C(=O)S-、-OC(=O)-、-C(=O)O-、-NRL1a
C(=S)-、-C(=S)NRL1a
-、反式
-CRL1b
=CRL1b
-、順式
-CRL1b
=CRL1b
-、-CºC-、-OC(RL1b
)2
-、-C(RL1b
)2
O-、-NRL1a
C(RL1b
)2
-、-C(RL1b
)2
NRL1a
-、-SC(RL1b
)2
-、-C(RL1b
)2
S-、-S(=O)2
O-、-OS(=O)2
-、-S(=O)2
NRL1a
-、-NRL1a
S(=O)2
-或可任選取代的C1-20
烴鏈,其中該烴鏈中一或多個碳原子可任選地由-O-、-S-、-NRL1a
-、-C(=O)-、NRL1a
C(=O)-、-NRL1a
C(=O)O-、-C(=O)NRL1a
-、-OC(=O)NRL1a
-、-SC(=O)-、-C(=O)S-、-OC(=O)-、-C(=O)O-、-NRL1a
C(=S)-、-C(=S)NRL1a
-、反式
-CRL1b
=CRL1b
-、順式
-CRL1b
=CRL1b
-、-CºC-、-S(=O)2
O-、-OS(=O)2
-、-S(=O)2
NRL1a
-或-NRL1a
S(=O)2
-取代,其中RL1a
是氫、可任選取代的C1-6
烷基,或一氮保護基,或是RL1a
亦可與鄰近的碳原子連結以形成一可任選取代的雜環;且其中各RL1b
係獨立選自於由氫、鹵素、可任選取代的C1-10
烷基、可任選取代的烯基、可任選取代的炔基、可任選取代的碳環(carbocyclyl)、可任選取代的雜環基、可任選取代的芳香基、可任選取代的雜芳基所組成的群組;或是RL1b
可與鄰近的碳、氮或氧原子連結以形成一可任選取代的碳環或雜環;或是二RL1b
化學基團可連結以形成一可任選取代的碳環或可任選取代的雜環;且L2
是一源自於能與載體及L1
交互反應之交聯劑(crosslinking reagent)的官能基。
在另一實施方式中,連結子包含至少一硫原子、羧酸酯基(carboxylate group)、醯胺基(amide group)、氨基甲酸酯基(carbamate group)、碳酸基(carbonate group)、硫代氨基甲酸酯基(thiocarbamate group)、硫碳酸類(thiocarbonate group)、硫醚基(thioether group)、丁二醯胺基(succinamide group)、正-羥基丁二醯胺基(n-hydroxy succinamide group)或其組合物。
在另一實施方式中,載體可以是蛋白、脂質、脂質化蛋白、病毒、胜肽或醣肽之樹枝狀聚合物(dendrimer)。在某些實施例中,載體是一包含T細胞抗原決定位置(epitope)的胜肽。
載體可以是一蛋白,選自由破傷風類毒素(tetanus toxoid, TT)、白喉類毒素(diphtheria toxoid, DT)、白喉類毒素交互反應物質197 (diphtheria toxin cross-reacting material 197, CRM197)、破傷風類毒素之片段C (fragment C of TT)、鍵孔血藍蛋白(Keyhole limpet hemocyanin, KLH)、胎牛血清白蛋白(bovine serum albumin, BSA)、蛋白D (protein D)、外膜蛋白(outer-membrane protein, OMP)及肺炎球菌溶血素(pneumolysin)所組成之群組。
在另一實施方式中,載體蛋白係選自由TT、DT及CRM197所組成的群組。在另一實施方式中,載體蛋白是CRM197,且聚醣共軛物具有式(III)的化學結構:其中, m是一介於1到38的正整數;且 若R1
是-OH,則R2
不是-CH3
;若R2
是-CH3
,則R1
不是-OH。
「m」一詞在本說明書中係一介於1至38的正整數。在本發明一實施方式中,m是一介於1至30的正整數,或一介於 1至20的正整數。舉例來說,m可以是1、2、3、4、6、8、10、15、20、30或38。
本發明的另一態樣是關於一聚醣共軛物之混合物,其係包含至少二種上述之聚醣共軛物。在某些實施方式中,聚醣混合物之w的平均值約由1.0到38.0,或約由1.0到10.0,或約為5.7、4.9、2.9、2.8或3.1。
免疫組合物可非必要性地包含一佐劑。佐劑可以是一能與樹突細胞之CD1d分子結合的醣脂。在某些實施方式中,佐劑可以是C34、Gluco-C34、7DW8-5、C17、C23、C30、α-神經醯胺半乳糖(α-galactoceramide)、鋁鹽、鯊烯(Squalene)、MF59或QS-21。
免疫組合物包含一免疫或藥學有效量的上述聚醣共軛物。
在另一態樣中,本發明是關於一種用以使個體產生對抗癌症之免疫反應的免疫組合物。癌症可以選自由腦癌、肺癌、乳癌、口腔癌、食道癌、胃癌、肝癌、膽管癌、胰臟癌、大腸直腸癌、腎臟癌、骨癌、皮膚癌、子宮頸癌、卵巢癌及前列腺癌所組成的群組。或者是,本發明是關於上述免疫組合物的用途,其係可用以製備一藥物以治療癌症病患,其中該免疫組合物可誘發癌細胞產生細胞毒殺反應、引發對抗癌症的免疫反應、產生可專一結合及/或中和一或多種癌細胞表面抗原的抗體,其中該一或多種癌細胞表面抗原係選自由Globo H、SSEA-3及SSEA-4所組成的群組。
在本發明一實施方式中,所述抗體主要是IgG抗體。免疫組合物主要可用以引發IgG1、IgG2b、IgG2c及IgG3的表現。
在再一態樣中,本發明是關於一種可對抗上述免疫組合物的單株抗體。
在另一態樣中,本發明是關於一種包含上述免疫組合物及一藥學上可接受之賦形劑的癌症疫苗。癌症疫苗可以包含單一劑量或多劑量之本發明聚醣共軛物、該聚醣共軛物之混合物或其免疫組合物。癌症疫苗可用以治療或降低個體罹患癌症之風險。癌症疫苗可包含用以闡述使用方法及告知個體或醫療人員處方訊息的相關資訊。該些資訊可由美國食品藥物管理局(U.S. Food and Drug Administration, FDA)等監管機構取得。癌症疫苗亦可具選擇性地包含用以投予化合物或組合物的器材,舉例來說,用以非口服投予的注射器。
在另一態樣中,本發明是關於用以治療及/或減少個體罹患癌症風險的方法,該方法包含對有需要之個體投予一治療有效量之上述免疫組合物或癌症疫苗。
該治療可減少腫瘤體積大小、消除惡性細胞、抑制轉移、防止癌症復發、減少或殺死轉移性癌症、延長存活時間及/或延長進展成腫瘤的時間。
該治療更可包含在投予上述免疫組合物或癌症疫苗之前、期間或之後對該個體投予額外的治療。額外的治療可以是一化療藥劑或一放射線治療。
在另一實施方式中,本發明是關於一種對一哺乳動物(例如人類病患)進行免疫接種使其能對抗癌症之方法,該方法包含對該哺乳動物投予一藥學有效量之上述免疫組合物或癌症疫苗。可利用皮下注射方式對該哺乳動物投予該免疫組合物或癌症疫苗。
所述癌症包含,但不限於,腦癌、肺癌、乳癌、口腔癌、食道癌、胃癌、肝癌、膽管癌、胰臟癌、大腸直腸癌、腎臟癌、骨癌、皮膚癌、子宮頸癌、卵巢癌及前列腺癌。
在另一態樣中,本發明是關於用以合成上述聚醣的方法。
在另一態樣中,本發明是關於用以製備上述免疫組合物或癌症疫苗的方法。在本發明一實施方式中,用以製備上述免疫組合物的方法包含下列步驟: (i)提供式(X)之化合物:式(X) 其中R1
、R2
、RA
及RB
分別如式(II)之定義;若R1
是-OH,則R2
不是-CH3
;若R2
是-CH3
,則R1
不是-OH; (ii)令式(X)之化合物與一胺基活化的(amino-active)雙功能連結子反應,以製備一第一反應產物;以及 (iii)令該第一反應產物與一載體蛋白反應,以製備一聚醣共軛物;以及 (iv)非必要性地混合一佐劑以製備本發明組合物。
在本發明一實施方式中,該胺基活化的雙功能連結子是一具有4到6個碳原子的二羧酸(dicarboxylic acid)。
上述發明內容僅用以闡述本發明某些實施方式。本發明其餘技術特徵及實施態樣可進一步參閱本揭示內容、圖式、實施例及申請專利範圍。
化學物定義
本揭示內容之化學元素及特定的官能基皆係依照第75版之Handbook of Chemistry and Physics
,CAS版本的化學元素週期表所定義。此外,有機化學、特定官能基及相關化學反應可參見Thomas Sorrell,Organic Chemistry
, University Science Books, Sausalito, 1999;Smith and March,March’s Advanced Organic Chemistry
, 第5版本, John Wiley & Sons, Inc., New York, 2001;Larock,Comprehensive Organic Transformations
, VCH Publishers, Inc., New York, 1989;及Carruthers,Some Modern Methods of Organic Synthesis
,第3版本, Cambridge University Press, Cambridge, 1987。
本說明書所述之化合物可包含一或多非對稱中心,且可以不同異構物形式(例如,鏡像異構物及/或非鏡像異構物)存在。舉例來說,本揭示內容所述之化合物可以是單獨存在的鏡像異構物、非鏡像異構物或幾何異構物,亦可以是立體異構物之混合物(包含外消旋混合物及包含一或多種立體異構物之混合物)。可利用本所屬領域習知技藝人士所熟知之方法由混合物中分離各異構物,包含掌性高壓液相層析法(high pressure liquid chromatography, HPLC)及掌性鹽類的形成及結晶;或是利用非對稱合成法來製備異構物。舉例來說,相關資訊可參見Jacqueset al.
,Enantiomers, Racemates and Resolutions
(Wiley Interscience, New York, 1981);Wilenet al.
,Tetrahedron
33:2725 (1977);Eliel,Stereochemistry of Carbon Compounds
(McGraw–Hill, NY, 1962);及Wilen,Tables of Resolving Agents and Optical Resolutions
p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972)。本發明亦包含上述化合物,其可以單一形式存在或是由不同異構物所組成之組合物形式存在。
當列舉一數值範圍時,該數值範圍包含所述範圍內之各數值及次範圍。舉例來說,「C1-6
」包含C1
、C2
、C3
、C4
、C5
、C6
、C1-6
、C1-5
、C1-4
、C1-3
、C1-2
、C2-6
、C2-5
、C2-4
、C2-3
、C3-6
、C3-5
、C3-4
、C4-6
、C4-5
及C5-6
。
在本說明書中,「烷基」(Alkyl)是指一具有1到20個碳原子之直鏈型或支鏈型飽和烴基的自由基(C1-20
烷基)。在某些實施方式中,烷基具有1到10個碳原子(C1-10
烷基)、1到9個碳原子(C1-9
烷基)、1到8個碳原子(C1-8
烷基)、1到7個碳原子(C1-7
烷基)、1到6個碳原子(C1-6
烷基)、1到5個碳原子(C1-5
烷基)、1到4個碳原子(C1-4
烷基)、1到3個碳原子(C1-3
烷基)或1到2個碳原子(C1-2
烷基)。烷基亦可指1個碳原子(C1
烷基)。
在某些實施方式中,烷基具有2到6個碳原子(C2-6
烷基)。例示性的C1-6
烷基包含,但不限於,甲基(methyl, C1
)、乙基(ethyl, C2
)、正丙基(n-
propyl, C3
)、異丙基(iso
-propyl, C3
)、正丁基(n-
butyl, C4
)、三級丁基(tert-
butyl, C4
)、二級丁基(sec-
butyl, C4
)、異丁基(iso-
butyl, C4
)、正戊基(n-
pentyl, C5
)、3-戊基(3-pentanyl, C5
)、3-甲基-1-丁基(amyl, C5
)、新戊基(neopentyl, C5
)、3-甲基-2-丁基(3-methyl-2-butanyl, C5
)、叔戊基(tertiary amyl, C5
)、正己基(n-
hexyl, C6
)、正庚基(n-
heptyl, C7
)及正辛基(n-
octyl, C8
)等。除非另有定義,否則各烷基皆可獨立以任選取代基取代,即烷基可為無取代基的烷基(一「無取代烷基」)或以一或多取代基取代的烷基(一「有取代烷基」)。在某些實施方式中,烷基是無取代基的C1-10
烷基(例如-CH3
)。在某些實施方式中,烷基是具有取代基的C1-10
烷基。
在本說明書中,「烯基」(Alkenyl)是指具有2到20個碳原子、一或多碳-碳雙鍵且無三鍵之直鏈型或支鏈型烴基的自由基(C2-20
烯基)。烯基可以具有2到10個碳原子(C2-10
烯基)、2到9個碳原子(C2-9
烯基)、2到8個碳原子(C2-8
烯基)、 2到7個碳原子(C2-7
烯基)、2到6個碳原子(C2-6
烯基)、2到5個碳原子(C2-5
烯基)、2到4個碳原子(C2-4
烯基)、2到3個碳原子(C2-3
烯基)或2個碳原子(C2
烯基)。該一或多個碳-碳雙鍵可以位於中間(例如2-丁烯基, 2-butenyl)或末端(例如1-丁烯基, 1-butenyl)。例示性的C2-4
烯基包含,但不限於,乙烯基(ethenyl, C2
)、1-丙烯基(1-propenyl, C3
)、2-丙烯基(2-propenyl, C3
)、1-丁烯基(1-butenyl, C4
)、2-丁烯基(2-butenyl, C4
)及丁二烯基(butadienyl, C4
)等。例示性的C2-6
烯基包含,但不限於,C2-4
烯基、戊烯基(pentenyl, C5
)、戊二烯基(pentadienyl, C5
)、己烯基(hexenyl, C6
)、庚烯基(heptenyl, C7
)、辛烯基(octenyl, C8
)及辛二烯基(octatrienyl, C8
)等。除非另有定義,否則各烯基皆可分別以任選取代基取代,即烯基可為無取代基的烯基(一「無取代烯基」)或以一或多取代基取代的烯基(一「有取代烯基」)。舉例來說,烯基可以是無取代基的C2-10
烯基,或是具有取代基的C2-10
烯基。
在本說明書中,「炔基」(Alkynyl)是指具有2到20個碳原子、一或多碳-碳三鍵及非必要性之一或多雙鍵之直鏈型或支鏈型烴基的自由基(C2-20
炔基)。在某些實施方式中,炔基可以具有2到10個碳原子(C2-10
炔基)、2到9個碳原子(C2-9
炔基)、2到8個碳原子(C2-8
炔基)、2到7個碳原子(C2-7
炔基)、2到6個碳原子(C2-6
炔基)、2到5個碳原子(C2-5
炔基)、2到4個碳原子(C2-4
炔基)、2到3個碳原子(C2-3
炔基)或2個碳原子(C2
炔基)。該一或多個碳-碳三鍵可以位於中間(例如2-丁炔基, 2-butynyl)或末端(例如1-丁炔基, 1-butynyl)。例示性的C2-4
炔基包含,但不限於,乙炔基(ethynyl, C2
)、1-丙炔基(1-propynyl, C3
)、2-丙炔基(2-propynyl, C3
)、1-丁炔基(1-butynyl, C4
)及2-丁炔基(2-butynyl, C4
)等。例示式的C2-6
炔基包含,但不限於,上述C2-4
炔基、戊炔基(pentynyl, C5
)、己炔基(hexynyl, C6
)、庚炔基(heptynyl, C7
)及辛炔基(octynyl, C8
)等。除非另有定義,否則各炔基皆可獨立以任選取代基取代,即炔基可為無取代基的炔基(一「無取代炔基」)或以一或多取代基取代的炔基(一「有取代炔基」)。舉例來說,炔基可以是無取代基的C2-10
烯基,或是具有取代基的C2-10
炔基。
在本說明書中,「雜環基」(Heterocyclyl)或「雜環」(heterocyclic)是指具有環碳原子(ring carbon atom)及1到4個環雜原子(ring heteroatom)之3到10員非芳香族環狀系統的自由基,其中各雜原子可以分別選自由氮、氧、硫、硼、磷及矽所組成的群組(3-10員雜環基)。在某些實施方式中,雜原子是分別選自由氮、硫及氧所組成的群組。在包含一或多氮原子之雜環基中,可利用碳或氮原子來進行連接。雜環基可以是一單環(單環雜環基, monocyclic heterocyclyl)或一融合、鍵結或螺旋環狀系統,例如雙環系統(雙環雜環基),且可以是飽和型或不飽和型。雜環雙環系統可在一或雙環中包含一或多雜原子。「雜環基」(Heterocyclyl)亦可包含環狀系統,其中雜環可利用碳環或雜環上的自由基或鍵結與一或多碳環融合,或利用雜環上的自由基或鍵結與一或多芳香基或雜芳香基融合,其中該連接點是位於雜環上;在此情況下,環中成員的數量即為該雜環系統中該環中成員的數量。除非另有定義,否則各雜環基皆可分別以任選取代基取代,即雜環基可為無取代基的雜環基(一「無取代雜環基」)或以一或多取代基取代的雜環基(一「有取代雜環基」)。舉例來說,雜環基可以是無取代基之3-10員的雜環基,亦可以是具有取代基之3-10員的雜環基。
在本說明書中,「芳香基」(Aryl)是指具有單環或多環(例如雙環或三環)之4n+2芳環系統(例如共用6、10或14 π電子的環狀陣列)的自由基,其中該芳環系統具有6-14個環碳原子及0個雜原子(C6-14
芳香基)。在某些實施方式中,芳香基可以具有6個環碳原子(C6
芳香基,例如苯基)、10個環碳原子(C10
芳香基,例如1-萘基(1-naphthyl)及2-萘基等萘基)或14個環碳原子(C14
芳香基,例如蒽基(anthracyl))。「芳香基」(Aryl)亦包含環狀系統,其中芳環可透過芳環上的自由基或鍵結與一或多碳環或雜環融合;在該些情況下,碳原子的數量即為芳環系統中碳原子的數量。除非另有定義,否則各芳香基皆可分別以任選取代基取代,即芳香基可為無取代基的芳香基(一「無取代芳香基」)或以一或多取代基取代的芳香基(一「有取代芳香基」)。舉例來說,雜環基可以是無取代基之C6-14
芳香基,亦可以具是有取代基之C6-14
芳香基。
在本說明書中,烷基、烯基、炔基、碳環、雜環基、芳香基及雜芳香基等二價橋接基(divalent bridging group)更可指以-ene結尾之官能基團,例如亞烷基(alkylene)、伸烯基(alkenylene)、亞炔基(alkynylene)、亞碳環(carbocyclylene)、亞雜環(heterocyclylene)、亞芳基(arylene)及亞雜芳基(heteroarylene)。
在本說明書中,「烷氧基」(alkoxy或alkyloxy)是指一-O-烷基自由基,其中該烷基為可任選取代的烷基。例示性的烷氧基包含,但不限於,甲氧基(methoxy)、乙氧基(ethoxy)、正丙氧基(n-propoxy)、異丙氧基(isopropoxy)、正丁氧基(n-butoxy)、異丁氧基(iso-butoxy)、二級丁氧基(sec-butoxy)及三級丁氧基(tert-butoxy)。
「芳氧基」(aryloxy)在本說明書是指一-O-芳香基,其中該芳香基為可任選取代的芳香基。
在本說明書中,「可任選取代的」(optionally substituted)一詞是指一有取代的或無取代的官能基。
烷基、烯基、炔基、碳環、雜環、芳香基及雜芳香基在本說明書中,可為任選取代的(例如有取代的或無取代的烷基、有取代的或無取代的烯基、有取代的或無取代的炔基、有取代的或無取代的碳環、有取代的或無取代的雜環、有取代的或無取代的芳香基,或是有取代的或無取代的雜芳香基)。一般來說,「有取代的」(substituted)一詞不論是否以「可任選的」(optionally)一詞加以修飾,皆係指化學基團(例如碳或氮原子)中以可允許的取代基置換至少一個氫原子,例如取代後會產生穩定之化合物(例如不會自動進行重組、環化、去除等反應的化合物)的取代。除非另有定義,否則一「有取代的」(substituted)基團於一或多個可取代位置具有一個取代基,且當多於一個位置被取代時,各位置的取代基可以是相同或不同的。有取代的」(substituted)一詞亦包含以有機化合物中所有可允許之取代基所置換的取代,該些取代基皆會產生穩定的化合物。本發明可利用單一或所有組合取代以產生穩定的化合物。為此,氮原子等雜原子可具有氫取代基及/或任何上述之適合的取代基,藉以穩定雜原子的價數並產生穩定的官能基。
「鹵」(Halo)或「鹵素」(halogen)是指氟(fluorine, fluoro, -F)、氯(chlorine, chloro, -Cl)、溴(bromine, bromo, -Br)或碘(iodine, iodo, -I)。
「醯基」(Acyl)是指一選自由-C(=O)Raa
,-CHO、-CO2
Raa
、-C(=O)N(Rbb
)2
、-C(=NRbb
)Raa
、-C(=NRbb
)ORaa
、-C(=NRbb
)N(Rbb
)2
、-C(=O)NRbb
SO2
Raa
、-C(=S)N(Rbb
)2
、-C(=O)SRaa
及-C(=S)SRaa
所組成之群組的官能基,其中Raa
及Rbb
分別如上述定義。
在價數允許的情況下,氮原子可以是取代的或無取代的,且包含一級、二級、三級及四級氮原子。例示性的氮原子取代基包含,但不限於,氫、-OH、-ORaa
、-N(Rcc
)2
、-CN、-C(=O)Raa
、-C(=O)N(Rcc
)2
、-CO2
Raa
、-SO2
Raa
、-C(=NRbb
)Raa
、-C(=NRcc
)ORaa
、-C(=NRcc
)N(Rcc
)2
、-SO2
N(Rcc
)2
、-SO2
Rcc
、-SO2
ORcc
、-SORaa
、-C(=S)N(Rcc
)2
、-C(=O)SRcc
、-C(=S)SRcc
、-P(=O)2
Raa
、-P(=O)(Raa
)2
、-P(=O)2
N(Rcc
)2
、-P(=O)(NRcc
)2
、C1-10
烷基、C1-10
全鹵烷基(perhaloalkyl)、C2-10
烯基、C2-10
炔基、C3-10
碳環、3-14員之雜環基、C6-14
芳香基及5-14員之雜芳香基,或是加入二個固定於氮原子之Rcc
基團以形成一3-14員之雜環或5-14員之異芳環,其中各烷基、烯基、炔基、碳環、雜環、芳香基及雜芳香基可分別以0、1、2、3、4或5 Rdd
基團取代,且其中Raa
、Rbb
、Rcc
及Rdd
分別如上述之定義。
在某些實施方式中,氧原子上的取代基可以是氧保護基(亦指一羥基保護基)。氧保護基包含,但不限於,-Raa
、-N(Rbb
)2
、-C(=O)SRaa
、-C(=O)Raa
、-CO2
Raa
、-C(=O)N(Rbb
)2
、-C(=NRbb
)Raa
、-C(=NRbb
)ORaa
、-C(=NRbb
)N(Rbb
)2
、-S(=O)Raa
、-SO2
Raa
、-Si(Raa
)3 、
-P(Rcc
)2
、-P(Rcc
)3
、-P(=O)2
Raa
、-P(=O)(Raa
)2
、-P(=O)(ORcc
)2
、-P(=O)2
N(Rbb
)2
及-P(=O)(NRbb
)2
,其中Raa
、Rbb
及Rcc
分別如上述定義。氧保護基為本所屬領域習知技藝人士所熟知之化學保護基團,且包含該些闡述於Protecting Groups in Organic Synthesis
, T. W. Greene and P. G. M. Wuts,第3版, John Wiley & Sons, 1999的保護基團,該文獻在此一併納入以供參照。
例示性的氧保護基包含,但不限於,甲基、甲氧甲基(methoxylmethyl, MOM)、甲硫甲基(methylthiomethyl, MTM)、叔丁硫甲基(t
-butylthiomethyl)、(苯二甲矽烷基)甲氧甲基((phenyldimethylsilyl)methoxymethyl, SMOM)、苄氧甲基(benzyloxymethyl, BOM)、對甲氧基苄氧甲基(p
-methoxybenzyloxymethyl, PMBM)、(4-甲氧基苯氧基)甲基((4-methoxyphenoxy)methyl,p
-AOM)、癒創木酚甲基(guaiacolmethyl, GUM)、叔丁氧甲基(t
-butoxymethyl)、4-戊烯基氧甲基(4-pentenyloxymethyl, POM)、矽烷氧甲基(siloxymethyl)、2-甲氧基乙氧基甲基(2-methoxyethoxymethyl, MEM),、2,2,2-三氯乙氧基甲基(2,2,2-trichloroethoxymethyl)、雙(2-氯乙氧基)甲基(bis(2-chloroethoxy)methyl)、2-(三甲基矽烷基)乙氧甲基(2-(trimethylsilyl)ethoxymethyl, SEMOR)、四氫哌喃基(tetrahydropyranyl, THP)、3-溴四氫哌喃基(3-bromotetrahydropyranyl)、四氫噻喃基(tetrahydrothiopyranyl)、1-甲氧基環己基(1-methoxycyclohexyl)、4-甲氧基四氫哌喃基(4-methoxytetrahydropyranyl, MTHP)、4-甲氧基四氫噻喃基(4-methoxytetrahydrothiopyranyl)、S,S-二氧-4-甲氧基四氫噻喃基(4-methoxytetrahydrothiopyranyl S,S-dioxide)、1-[(2-氯-4-甲基)苯基]-4-甲氧基哌啶-4-基(1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl, CTMP)、1,4-二噁烷-2-基(1,4-dioxan-2-yl)、四氫喃基(tetrahydrofuranyl)、四氫噻吩基(tetrahydrothiofuranyl)、2,3,3a,4,5,6,7,7a-八氫-7,8,8-三甲基-4,7-亞甲基苯呋喃-2-基(2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl)、1-乙氧乙基(1-ethoxyethyl)、1-(2-氯乙氧基)乙基(1-(2-chloroethoxy)ethyl)、1-甲基-1-甲氧乙基(1-methyl-1-methoxyethyl)、1-甲基-1-苄氧乙基(1-methyl-1-benzyloxyethyl)、1-甲基-1-苄氧基-2-氟乙基(1-methyl-1-benzyloxy-2-fluoroethyl)、2,2,2,-三氯乙基(2,2,2-trichloroethyl)、2-三甲基矽烷乙基(2-trimethylsilylethyl)、2-(苯氫硒基)乙基(2-(phenylselenyl)ethyl)、叔丁基(t-
butyl)、烯丙基(allyl)、對氯苯基(p
-chlorophenyl)、對甲氧苯基(p-
methoxyphenyl)、2,4-二硝基苯基(2,4-dinitrophenyl)、苄基(benzyl (Bn))、對甲氧苄基(p-
methoxybenzyl)、3,4-二甲氧苄基(3,4-dimethoxybenzyl)、鄰硝基苄基(o
-nitrobenzyl)、對硝基苄基(p-
nitrobenzyl)、對鹵代苄基(p-
halobenzyl)、2,6-二氯苄基(2,6-dichlorobenzyl)、對氰基苄基(p-
cyanobenzyl)、對苯基苄基(p-
phenylbenzyl)、2-皮考基(2-picolyl)、4-皮考基(4-picolyl)、3-甲基-2-皮考基N-環氧基(3-methyl-2-picolylN
-oxido)、二苯甲基(diphenylmethyl)、p,p’
-二硝基二苯甲基(p,p’
-dinitrobenzhydryl)、5-二苯環庚基(5-dibenzosuberyl)、三苯甲基(triphenylmethyl)、α-萘基二苯甲基(α-naphthyldiphenylmethyl)、對甲氧苯基二苯甲基(p
-methoxyphenyldiphenylmethyl)、二(對甲氧苯基)苯基甲基(di(p-
methoxyphenyl)phenylmethyl)、三(對甲氧苯基)甲基(tri(p-
methoxyphenyl)methyl)、4-(4’-溴苯甲醯甲基氧基苯基)二苯基甲基(4-(4’-bromophenacyloxyphenyl)diphenylmethyl)、4,4′,4″-三(4,5-二氯鄰苯二甲醯亞氨基苯基)甲基(4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl)、4,4′,4″-三(乙醯丙醯基氧基苯基)甲基(4,4′,4″-tris(levulinoyloxyphenyl)methyl)、4,4′,4″-三(苯甲醯基氧基苯基)甲基(4,4′,4″-tris(benzoyloxyphenyl)methyl)、3-(咪唑-1-基)雙(4′,4″-二甲氧苯基)甲基(3-(imidazole-1-yl)bis(4′,4″-dimethoxyphenyl)methyl)、1,1-雙(4-甲氧基苯基)- 1′-芘基甲基(1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl)、9-蒽基(9-anthryl)、9-(9-苯基)占噸基(9-(9-phenyl)xanthenyl)、9-(9-苯基-10-氧代)蒽基(9-(9-phenyl-10-oxo)anthryl)、1,3-苯並二硫雜環戊-2-基、(1,3-benzodithiolan-2-yl)、苯並異噻唑基S,S-二環氧基(benzisothiazolyl S,S-dioxide)、三甲基矽烷基(trimethylsilyl, TMS)、三乙矽烷基(triethylsilyl, TES)、三異丙矽烷基(triisopropylsilyl, TIPS)、二甲異丙矽烷基(dimethylisopropylsilyl, IPDMS)、二乙異丙矽烷基(diethylisopropylsilyl, DEIPS)、二甲己矽烷基(dimethylthexylsilyl)、叔丁基二甲矽烷基(t-
butyldimethylsilyl, TBDMS)、叔丁基二苯矽烷基(t-
butyldiphenylsilyl, TBDPS)、三苄基矽烷基(tribenzylsilyl)、三對二甲苯矽烷基(tri-p-
xylylsilyl)、三苯矽烷基(triphenylsilyl)、二苯甲矽烷基(diphenylmethylsilyl, DPMS)、叔丁基甲氧苯矽烷基(t
-butylmethoxyphenylsilyl, TBMPS)、甲酸酯(formate)、苯甲醯甲酸酯(benzoylformate)、乙酸酯(acetate)、氯乙酸酯(chloroacetate)、二氯乙酸酯(dichloroacetate)、三氯乙酸酯(trichloroacetate)、三氟乙酸酯(trifluoroacetate)、甲氧乙酸酯(methoxyacetate)、三苯甲氧乙酸酯(triphenylmethoxyacetate)、苯氧乙酸酯(phenoxyacetate)、對氯苯氧乙酸酯(p-
chlorophenoxyacetate)、3-苯丙酸酯(3-phenylpropionate)、4-氧代戊酸酯(乙醯丙酸酯, 4-oxopentanoate, levulinate), 4,4-(亞乙基二硫代)戊酸酯(4,4-(ethylenedithio)pentanoate)、乙醯丙醯基二硫縮醛(levulinoyldithioacetal)、新戊酸酯(pivaloate)、金剛烷二甲酸酯(adamantoate)、巴豆酸酯(crotonate)、4-甲氧基巴豆酸酯(4-methoxycrotonate)、苯甲酸酯(benzoate)、對苯基苯甲酸酯(p-
phenylbenzoate)、2,4,6-三甲基苯甲基酯(2,4,6-trimethylbenzoate, mesitoate)、碳酸甲酯(methyl carbonate)、碳酸9-茀基甲酯(9-fluorenylmethyl carbonate, Fmoc)、碳酸乙酯(ethyl carbonate)、碳酸2,2,2-三氯乙酯(2,2,2-trichloroethyl carbonate, Troc)、碳酸2-(三甲基矽烷基)乙酯(2-(trimethylsilyl)ethyl carbonate, TMSEC)、碳酸2-(苯基磺醯基)乙酯(2-(phenylsulfonyl) ethyl carbonate, Psec)、碳酸2-(三苯基磷鎓基)乙酯(2-(triphenylphosphonio) ethyl carbonate, Peoc)、碳酸異丁酯(isobutyl carbonate)、碳酸乙烯酯(vinyl carbonate)、碳酸烯丙酯(allyl carbonate)、碳酸叔丁酯(t
-butyl carbonate, BOC)、碳酸對硝基苯酯(p-
nitrophenyl carbonate)、碳酸苄酯(benzyl carbonate)、碳酸對甲氧基苄酯(p-
methoxybenzyl carbonate)、碳酸3,4-二甲氧基苄酯(3,4-dimethoxybenzyl carbonate)、碳酸鄰硝基苄酯(o
-nitrobenzyl carbonate)、碳酸對硝基苄酯(p-
nitrobenzyl carbonate)、硫代碳酸S-苄酯(S-
benzyl thiocarbonate)、碳酸4-乙氧基-1-萘酯(4-ethoxy-1-napththyl carbonate)、二硫代碳酸甲酯(methyl dithiocarbonate)、2-碘代苯甲酸酯(2-iodobenzoate)、4-疊氮丁酸酯(4-azidobutyrate)、4-硝基-4-甲基戊酸酯(4-nitro-4-methylpentanoate)、鄰(二溴甲基)苯甲酸酯(o-
(dibromomethyl)benzoate)、2-甲醯基苯磺酸酯(2-formylbenzenesulfonate)、2-(甲硫基甲氧基)乙基碳酸酯(2-(methylthiomethoxy)ethyl)、4-(甲硫基甲氧基)丁酸酯(4-(methylthiomethoxy)butyrate)、2-(甲硫基甲氧基甲基)苯甲酸酯(2-(methylthiomethoxymethyl)benzoate)、2,6-二氯-4-甲基苯氧基乙酸酯(2,6-dichloro-4-methylphenoxyacetate)、2,6-二氯-4-(1,1,3,3-四甲基丁基)苯氧基乙酸酯(2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate)、2,4-雙(1,1-二甲基丙基)苯氧基乙酸酯(2,4-bis(1,1-dimethylpropyl)phenoxyacetate)、氯二苯基乙酸酯(chlorodiphenylacetate)、異丁酸酯(isobutyrate)、單琥珀酸酯(monosuccinoate)、(E
)-2-甲基-2-丁烯酸酯((E
)-2-methyl-2-butenoate)、鄰(甲氧基羰基)苯甲酸酯(o-
(methoxyacyl)benzoate)、α-萘甲酸酯(α-naphthoate)、硝酸酯(nitrate)、N
,N,N’,N’
-四甲基二氨基磷酸烷基酯(alkylN
,N,N’,N’-
tetramethylphosphorodiamidate)、N-苯基氨基甲酸酯(alkylN
-phenylcarbamate)、硼酸酯(borate)、次磺酸二甲基瞵酯(dimethylphosphinothioyl)、次磺酸2,4二硝基苯酯(alkyl 2,4-dinitrophenylsulfenate)、硫酸酯(sulfate)、甲磺酸酯(methanesulfonate, mesylate)、苄磺酸酯(benzylsulfonate)及甲苯磺酸酯(tosylate, Ts)。
其他定義
除非本說明書另有定義,否則此處所用的科學與技術詞彙之含義與本發明所屬技術領域中具有通常知識者所理解與慣用的意義相同。此外,在不和上下文衝突的情形下,本說明書所用的單數名詞「一」(a或an)及「該」(the)均涵蓋該名詞的複數型;而所用的複數名詞時亦涵蓋該名詞的單數型。同時,在此處「一」(a或an)、「至少一」(at least one)及「一或多」(one or more)為可互換之詞彙。「包含」(comprising或including)及「具有」(having)亦為可互換之詞彙。
除非本說明書另有定義,否則本發明係利用本所屬領域習知技藝人士所熟知之分子生物學、微生物學、重組DNA及免疫學等傳統生物技術來進行相關實驗。該些技術可參見於先前文獻。舉例來說,Molecular Cloning A Laboratory Manual,第2版by Sambrook, Fritsch and Maniatis (Cold Spring Harbor Laboratory Press, 1989);DNA Cloning, Volumes I and II (D. N. Glover ed., 1985);Culture Of Animal Cells (R. I. Freshney, Alan R. Liss, Inc., 1987);Immobilized Cells And Enzymes (IRL Press, 1986);B. Perbal, A Practical Guide To Molecular Cloning (1984);the treatise, Methods In Enzymology (Academic Press, Inc., N.Y.);Gene Transfer Vectors For Mammalian Cells (J. H. Miller and M. P. Calos eds., 1987, Cold Spring Harbor Laboratory);Methods In Enzymology, Vols. 154 and 155 (Wu et al. eds.), Immunochemical Methods In Cell And Molecular Biology (Mayer and Walker, eds., Academic Press, London, 1987);Antibodies: A Laboratory Manual, by Harlow and Lane s (Cold Spring Harbor Laboratory Press, 1988);及Handbook Of Experimental Immunology, Volumes I-IV (D. M. Weir and C. C. Blackwell, eds., 1986)。
在本說明書中,「聚醣」(glycan)一詞是指一種多醣(polysaccharide)或寡醣(oligosaccharide)。聚醣在本說明書中是指諸如醣蛋白(glycoprotein)、醣脂(glycolipid)、醣肽(glycopeptide)、醣蛋白質體(glycoproteome)、肽聚醣(peptidoglycan)、脂多醣(lipopolysaccharide)及蛋白醣(proteoglycan)等複合醣體(glycoconjugate)的醣部份。聚醣通常僅包含單醣間的O-醣苷鍵(O-glycosidic linkage)。舉例來說,纖維素是一種由β-1,4-連結之D-葡萄糖所組成的聚醣(或更具體來說,葡聚醣),而幾丁質則是一種由β-1,4-連結之N-乙醯基-D-葡萄糖胺所組成的聚醣。聚醣可以是由單醣殘基組合而成的同或異聚合物,且可以直鏈或支鏈形式存在。聚醣可與蛋白質連結,形成醣蛋白或蛋白醣。聚醣多表現於細胞的外表面。O-及N-連結之聚醣主要表現於真核生物中,原核生物則較少。在序列段(sequon)中,N-連結之聚醣會與天門冬胺酸(asparagine)的R-基團氮(N)連結。該序列段是一Asn-X-Ser或Asn-X-Thr序列,其中X可以是堅果糖(praline)以外的任何胺基酸。
「抗原」(antigen)一詞在本說明書中是指任何可引發免疫反應的物質。
「免疫性」(immunogenicity)一詞在本說明書中是指一免疫原、抗原或疫苗刺激產生免疫反應的能力。
「CD1d」一詞在本說明書中是指一醣蛋白之CD1 (分化群1, cluster of differentiation 1)家族的一員,其中該醣蛋白會表現於不同人類抗原呈現細胞(antigen-presenting cell)的表面。呈現脂質的CD1d會活化自然殺手T細胞(natural killer T cell)。CD1d具有一深層的抗原結合溝槽,據以和醣脂抗原結合。表現於樹突細胞(dendritic cell)的CD1d分子可結合並呈現醣脂神經醯胺(Galactosylceramide, GalCer) 相似物,例如C34。
「抗原決定位置」(epitope)一詞在本說明書是指一抗原分子的部份,可與抗體或T細胞受器的抗原結合位置接觸。
「疫苗」(vaccine)一詞在本說明書是指一包含抗原的製劑,該抗原包含致病微生物(死毒或減毒)或其部份成分,例如蛋白、胜肽或多醣;該製劑可用以引發免疫反應以對抗由該微生物所造成的疾病。疫苗製劑可以是天然的、合成的或由重組DNA技術而得。
「抗原專一性」(antigen specific)一詞在本說明書是指一細胞族群的特性,當投予特定的抗原或抗原片段時,可造成特定細胞增生。
在本說明書中,「專一結合」(specifically binding)一詞是指結合對(binding pairs)(例如抗體及抗原)之間的交互作用。在不同情況下,可利用親合常數(affinity constant)來表示專一結合的程度,其中該親合常數約為每公升10-6
莫耳、每公升10-7
莫耳或每公升10-8
莫耳。
「流式細胞儀」(flow cytometry或FACS)一詞是指一種可用以檢驗懸浮於液體水柱之顆粒或細胞之物理及化學特性的技術,該技術主要是透過光學及電子偵測設備來進行分析。
除非本說明書另有定義,否則此處所用的科學與技術詞彙之含義與本發明所屬技術領域中具有通常知識者慣用者相同。此處選用及描述多種實施方式與實施例來解釋本發明之原理及應用性,藉使本技術領域中熟習此技藝者可據以實現本發明,並基於所欲的特定用途來利用本發明的各種實施方式與各種適當的變形。為闡述及揭示特定化學材料、細胞株、載體、動物、儀器設備、統計分析及方法,在此將本揭示內容所引用之公開文獻及專利納入作為參照。引用且/或討論這些文獻的目的僅在闡明本發明之實施方式,而非承認該文獻為此處所述之本發明的先前技術。
本發明實施方式
本發明是關於意外發現以經修飾之Globo H衍生物抗原與載體蛋白-白喉類毒素交互反應物質(diphtheria toxoid cross-reactive material, CRM197)連結後,與作為佐劑的醣脂C34合併使用,可引發強烈的IgG免疫反應,因而可專一性地辨識Globo H (GH)、Gb5及SSEA4。在某些實施方式中,修飾Globo H是指在Globo H還原端葡萄糖的C-6位置包含有一氟、一疊氮基(azido)或一鄰苯基(O-phenyl)。在某些實施方式中,修飾Globo H是指在其非還原端海藻糖之C-6位置包含有一疊氮基。由該些疫苗所產生的抗體可辨識GH表現腫瘤細胞(MCF-7),並引發與補體相關之細胞毒殺反應來對抗腫瘤細胞。本發明提供癌症疫苗研發領域一種新穎的策略方法。
本揭示內容是關於Globo H衍生物,其中各衍生物之還原及/或非還原端皆經過修飾處理。相較於天然的Globo H,該些Globo H衍生物可引發強烈的免疫反應(例如,引發對抗Globo H、Gb5及SSEA4的IgG抗體)。
化合物
本發明提供了數種具有經修飾之醣類抗原(Globo H)的新穎化合物、包含該些新穎化合物的聚醣共軛物、免疫組合物及疫苗。
在一態樣中,本發明是關於式(I)的化合物:或其鹽類, 其中, X1
是-OR或-SR,其中R是氫、或是氧或硫的保護基、可任選取代的C1-10
烷基、可任選取代的芳香基、可任選取代的醯基或可任選取代的亞胺基; R1
及R2
係分別選自由氫、鹵素、可任選取代的烷基、可任選取代的烯基、可任選取代的炔基、可任選取代的雜環基、可任選取代的芳香基、-N3
、-NO2
、-N(RB
)2
、-N(RA
)C(O)RA
、-ORA
、-OC(O)RA
、-SRA
、-C(O)N(RB
)2
、-CN、-C(O)RA
、-C(O)ORA
、-S(O)RA
、-SO2
RA
、-SO2
N(RB
)2
及-NHSO2
RB
所組成群組; RA
係選自由氫、可任選取代的烷基、可任選取代的烯基、可任選取代的炔基、可任選取代的雜環基、可任選取代的芳香基所組成的群組; RB
係選自由氫、可任選取代的烷基、可任選取代的烯基、可任選取代的炔基、可任選取代的雜環基、可任選取代的芳香基所組成的群組;以及 若R1
是-OH,則R2
不是-CH3
;若R2
是-CH3
,則R1
不是-OH。
在本發明一實施方式中,X1
具有α構型。在本發明另一實施方式中,X1
具有β構型。
在本發明另一實施方式中,X1
是選自由-ORA
、-OH及-O(保護基團)所組成的群組。在本發明另一實施方式中,X1
是-ORA
,其中RA
可以是無取代的C1-10
烷基、無取代的芳香基、無取代的醯基或無取代的亞胺基,或是其中RA
可以是有取代的C1-10
烷基、有取代的芳香基、有取代的醯基或有取代的亞胺基。
在本發明另一實施方式中,X1
是-SRA
。在本發明另一實施方式中,X1
是選自由-SH及-S(保護基團),以及-SCH3
所組成的群組。在本發明另一實施方式中,X1
是-SRA
,其中RA
可以是無取代的C1-10
烷基、無取代的芳香基、無取代的醯基或無取代的亞胺基,或是其中RA
可以是有取代的C1-10
烷基、有取代的芳香基、有取代的醯基或有取代的亞胺基。
在本發明另一實施方式中,X1
是C1-10
烷氧基、C1-3
烷氧基或甲氧基。在本發明另一實施方式中,X1
是α-甲氧基。
在本發明另一實施方式中,X1
是選自由α-甲硫基(alpha-thiomethyl)、β-甲硫基(beta-thiomethyl)、α-硫代甲苯基(alpha-thiocresyl)、β-硫代甲苯基(beta-thiocresyl)、α-叔-丁二苯矽氧基(alpha-t-butyldiphenylsilyloxy)、β-叔-丁二苯矽氧基(beta-t-butyldiphenylsilyloxy)及α-甲氧基(alpha-methoxy)所組成的群組。
在本發明另一實施方式中,R1
是-N3
或-N(RW
)2
,其中各RW
分別為氫或氮保護基。舉例來說,R1
可以是-NH2
。
在本發明另一實施方式中,R1
是-NHRW
或-N(RW
)2
,其中RW
是氮保護基。在某些實施方式中,R1
是選自由-N3
、-NH(Cbz)、-NH(Boc)、-NH(Fmoc)、-NHC(O)CCl3
、-NHC(O)CH3
及-N(C(O)CH3
)2
所組成的群組。
在本發明另一實施方式中,R2
是-N3
或-N(RW
)2
,其中各RW
分別為氫或氮保護基。在本發明另一實施方式中,R2
是-NH2
、-NHRW
或-N(RW
)2
,其中RW
是氮保護基。在本發明另一實施方式中,R2
是選自由-N3
、-NH(Cbz)、-NH(Boc)、-NH(Fmoc)、-NHC(O)CCl3
、-NHC(O)CH3
及-N(C(O)CH3
)2
所組成的群組。
在本發明另一實施方式中,R1
及R2
是相同的化學基團。
在本發明另一實施方式中,R1
是-OH。在本發明另一實施方式中,R1
是-OH且R2
是-CH2
F、-CH2
N3
、CH2
NO2
、-CH2
OH或-C≡CH。
在本發明另一實施方式中,R1
是-F且R2
是-CH3
,或是R1
是-N3
且R2
是-CH3
,或是R1
是-NO2
且R2
是-CH3
。
在本發明另一實施方式中,R1
是,且R2
是-CH3
;或是R1
是,且R2
是-CH3
。
例示性之式(I)化合物包含,但不限於, ; and.
可利用本所屬領域具有通常知識者所熟知之方法或本揭示內容所述方法來合成Globo H衍生物。或參酌美國專利US20140051127所述方法。
免疫組合物
在另一態樣中,本發明是關於一種免疫組合物,其係包含(a)一聚醣共軛物,包含至少一種與連結子結合的聚醣以及一載體,其中該至少一種聚醣是藉由連結子與載體形成共軛;以及(b)一非必要性之佐劑,其中該至少一種與連結子結合的聚醣具有式(II)之化學結構:其中R1
及R2
之定義分別如上所述。
在本發明一實施方式中,連結子是一異-或同-雙功能連結子。
在本發明另一實施方式中,連結子包含至少一硫原子、羧酸酯基、醯胺基、氨基甲酸酯基、碳酸基、硫代氨基甲酸酯基、硫碳酸基、硫醚、丁二醯胺、正-羥基丁二醯胺或其之任何組合。
在本發明另一實施方式中,連結子是,其中L1
是一鍵結、-O-、-S-、-NRL1a
-、-C(=O)-、-NRL1a
C(=O)-、-NRL1a
C(=O)O-、-C(=O)NRL1a
-、-OC(=O)NRL1a
-、 -SC(=O)-、-C(=O)S-、-OC(=O)-、-C(=O)O-、-NRL1a
C(=S)-、-C(=S)NRL1a
-、反式
-CRL1b
=CRL1b
-、順式
-CRL1b
=CRL1b
-、-CºC-、-OC(RL1b
)2
-、-C(RL1b
)2
O-、-NRL1a
C(RL1b
)2
-、-C(RL1b
)2
NRL1a
-、-SC(RL1b
)2
-、-C(RL1b
)2
S-、-S(=O)2
O-、-OS(=O)2
-、-S(=O)2
NRL1a
-、-NRL1a
S(=O)2
-或可任選取代的C1-20
烴鏈;可任選地,該烴鏈中一或多個碳原子可由–O–、–S–、–NRL1a
–、–C(=O)–、NRL1a
C(=O)–、–NRL1a
C(=O)O–、–C(=O)NRL1a
–、–OC(=O)NRL1a
–、 –SC(=O)–、–C(=O)S–、–OC(=O)–、–C(=O)O–、–NRL1a
C(=S)–、–C(=S)NRL1a
–、反式
–CRL1b
=CRL1b
–、順式
–CRL1b
=CRL1b
–、–CºC–、–S(=O)2
O–、–OS(=O)2
–、–S(=O)2
NRL1a
–或–NRL1a
S(=O)2
–取代,其中RL1a
是氫、可任選取代的C1-6
烷基或一氮保護基,或是RL1a
亦可與鄰近的碳原子連結以形成一可任選取代的雜環;且其中各RL1b
係分別選自於由氫、鹵素、可任選取代的C1-10
烷基、可任選取代的烯基、可任選取代的炔基、可任選取代的碳環、可任選取代的雜環基、可任選取代的芳香基、可任選取代的雜芳基所組成的群組;或是RL1b
可與鄰近的碳、氮或氧原子連結以形成一可任選取代的碳環或雜環;或是二RL1b
化學基團可連結以形成一可任選取代的碳環或可任選取代的雜環;且L2
是源自於能與載體及L1
交聯之交聯劑的官能基。
載體可以是蛋白、脂質、脂質化蛋白、病毒、胜肽或醣肽之樹枝狀聚合物。在某些實施例中,載體是一包含T細胞抗原決定位置的胜肽。
例示性的載體蛋白包含,但不限於,破傷風類毒素(tetanus toxoid, TT)、白喉類毒素(diphtheria toxoid, DT)、白喉類毒素交互反應物質197(CRM197)、破傷風類毒素的片段C (fragment C of TT)、鍵孔血藍蛋白(Keyhole limpet hemocyanin, KLH)、胎牛血清白蛋白(bovine serum albumin, BSA)、蛋白D (protein D)、外膜蛋白(outer-membrane protein, OMP)、肺炎球菌溶血素(pneumolysin)及其餘白喉類毒素交互反應物質或白喉類毒素的突變蛋白,例如CRM176、CRM228、CRM 45 (Uchida et al J. Biol. Chem. 218; 3838-3844, 1973)、CRM 9、CRM 45、CRM102、CRM 103及CRM107等本所屬領域習知技藝人士所熟知之突變形式。
在本發明另一實施方式中,聚醣共軛物具有式(IV-a)或(IV-b)的化學結構:其中m是一介於1到40的正整數。
在本發明另一實施方式中,m是一介於1到38的正整數,或一介於1到20的正整數。在本發明另一實施方式中,m是1、2、4、6、8、10、15、20、30或38。
在另一態樣中,本發明是關於一種聚醣共軛物之混合物,其係包含至少二種上述之聚醣共軛物。
在本發明另一實施方式中,Globo H衍生物可以藉由連結子與載體形成共軛,據以產生一聚醣共軛物。各共軛物可以包含相同或不同之Globo H衍生物的一或多個分子(例如1-40、1-20、1-25、1-30、5-20、5-25、5-30或5-35)。可利用本揭示內容所述方法或本所屬領域具有通常知識者所熟知之方法來製備聚醣共軛物。或可參見美國專利編號8,268,969所述方法。
本揭示內容之免疫組合物可包含一免疫有效量之本發明聚醣共軛物。
可利用本揭示內容所述方法或本所屬領域習知技藝人士所熟知之方法來合成本發明化合物。或可參見美國專利US20140051127。
本發明免疫組合物可包含一或多種佐劑。適用之佐劑乃為習知技藝人士所熟知(例如C34、7DW8-5、C17、C23、鋁鹽、鯊烯、MF59或QS-21)。
在本說明書中,「鋁佐劑」(alum adjuvant)一詞是指具有免疫佐劑活性的鋁鹽。該試劑在溶液中可吸附並沉澱蛋白抗原;所產生的沉澱物能減緩疫苗中抗原的釋放速度,進而改善疫苗的免疫性。
在本說明書中,「免疫佐劑」(immunologic adjuvant)一詞是指一種與免疫原連結的物質,可增加或修飾免疫原所產生的免疫反應。本揭示內容之α-醣脂神經醯胺相似物即是作為一種免疫佐劑,將疫苗投予至病患體內後,可刺激病患之免疫系統產生相關免疫反應,據以修飾或增加疫苗之效用。在一例示性之實施方式中,相似物C34是作為佐劑。C34及其餘α-醣脂神經醯胺相似物的結構及其應用可參見美國專利編號7,928,077。
「醣脂」(glycolipid)一詞在本說明書是指一種與醣接合之脂質,可作為細胞辨識的標記。
醣脂C34、C23及7DW8-5具有下列化學結構:
免疫組合物更可包含一藥學上可接受之賦形劑。上述免疫組合物可包含一藥學有效量之本發明聚醣共軛物。
在另一態樣中,本發明是關於一癌症疫苗,其係包含一上述之免疫組合物及一藥學上可接受之賦形劑。
本發明癌症疫苗可包含單一劑量或多劑量之本發明聚醣共軛物、該聚醣共軛物之混合物或其免疫組合物。癌症疫苗可用以治療或降低個體罹患癌症之風險。癌症疫苗可包含用以闡述使用方法及告知個體或醫療人員處方訊息的相關資訊。該些資訊可由美國食品藥物管理局(U.S. Food and Drug Administration, FDA)等監管機構取得。癌症疫苗亦可具選擇性地包含用以投予化合物或組合物的器材,舉例來說,用以非口服投予的注射器。
藥學配方
本發明免疫組合物可以與劑型相容且能產生治療、保護及免疫功效之劑量投予至個體。投予量將取決於欲進行治療之個體,包含,舉例來說,個體免疫系統合成抗體的能力,以及在特定情況下,產生細胞相關免疫反應(cell-mediated immune response)的能力。實際的活性成分投予量將取決於醫療人員的判斷。然而,本所屬領域習知技藝人士亦可決定適當的劑量範圍。投予劑量及方法會隨著實際情況不同而有所不同,然可包含一初次投予及後續之投予。疫苗的劑量亦會隨著投予路徑及宿主體積大小而改變
本發明免疫組合物亦可投予至動物體內,使其產生抗體,並利用該抗體來治療及診斷腫瘤。於動物(例如小鼠、兔子、山羊、綿羊或馬)體內製備單株及雙株抗體及其片段的方法乃為本所屬領域具有通常知識者所熟知之技術。舉例來說,可參見Harlow and Lane, (1988)Antibodies: A Laboratory Manua
l, Cold Spring Harbor Laboratory, New York。「抗體」(antibody)一詞包含完整的免疫球分子(immunoglobulin)及其片段,例如Fab、F(ab')2、Fv、scFv (單鏈抗體, single chain antibody)及dAb (域抗體, domain antibody; Ward, et. al. (1989)Nature
, 341, 544)。
本揭示內容之組合物可包含於一藥學組合物中,其中該藥學組合物更可包含習知技藝人士在閱讀本揭示內容後可推得之其他活性成份、載體、賦形劑或輔助藥劑。
藥學組合物可較佳地包含至少一種藥學上可接受的載體。在該種藥學組合物中,本揭示內容之組合物將形成「活性化合物」(active compound),或作為「活性試劑」(active agent)。一藥學上可接受的載體包含與投予藥物相容之溶劑、分散介質、塗膜、抗菌及抗真菌試劑、等滲及吸收延遲劑等。補充型活性化合物亦可包含於組合物中。一藥學組合物可依其投予路徑而配製為不同劑型。例示性的投予路徑包含非口服投予(例如靜脈注射、真皮注射、皮下注射)、口服投予(例如吸入)、穿皮投予(局部)、經黏膜投予及直腸投予。用以非口服、真皮或皮下投予的溶液或懸浮液可包含下列成份:一無菌之稀釋液(例如注射用水、生理食鹽水、定性油、聚乙二醇、甘油、丙二醇或其他合成溶劑)、抗菌試劑(例如苯甲醇或亞硫酸氫鈉)、抗氧化劑(例如抗壞血酸或亞硫酸氫鈉)、螯合劑(例如乙二胺四乙酸, ethylenediaminetetraacetic acid)、緩衝液(例如乙酸鹽、檸檬酸鹽或磷酸鹽)及用以調整張力的試劑(例如氯化鈉或葡萄糖)。可利用酸或鹼(例如鹽酸或氫氧化鈉)來調整pH值。非口服劑型可配製於安瓶、拋棄式注射器或玻璃或塑膠製成之多劑量瓶。
臨床應用
本發明是關於聚醣共軛物、免疫組合物或可用以治療一個體之癌症(例如肺癌、大腸癌、胰臟癌、膽道癌或子宮內膜癌)、良性瘤或血管新生等增生性疾病的疫苗。
亦可將本發明免疫組合物或疫苗投予至人類或動物體內以製備抗體,據以治療及診斷癌症。或是利用本發明免疫組合物或疫苗來製備可結合至Gloo H、SSEA-3及/或SSEA-4之抗體。於動物(例如小鼠、兔子、山羊、綿羊或馬)體內製備單株及雙株抗體及其片段的方法乃為本所屬領域具有通常知識者所熟知之技術。舉例來說,可參見Harlow and Lane, (1988)Antibodies: A Laboratory Manua
l, Cold Spring Harbor Laboratory, New York。「抗體」(antibody)一詞包含完整的免疫球分子(immunoglobulin)及其片段,例如Fab、F(ab')2、Fv、scFv (單鏈抗體, single chain antibody)及dAb (域抗體, domain antibody; Ward, et. al. (1989)Nature
, 341, 544)。
本發明聚醣共軛物、免疫組合物或疫苗可用以治療或診斷癌症,該些癌症包含,但不限於聽神經瘤(acoustic neuroma)、腺癌(adenocarcinoma)、腎上腺癌(adrenal gland cancer)、肛門癌(anal cancer)、淋巴管內瘤(lymphangiosarcoma)、淋巴管內皮肉瘤(lymphangioendotheliosarcoma)、血管肉瘤(angiosarcoma或hemangiosarcoma)、闌尾癌(appendix cancer)、良性單株球蛋白症(benign monoclonal gammopathy)、膽道癌(biliary cancer)、膽管癌(cholangiocarcinoma)、膀胱癌(bladder cancer)、乳癌(breast cancer或mammary cancer)、乳腺癌(adenocarcinoma of the breast)、乳突癌(papillary carcinoma of the breast)、乳髓質癌(medullary carcinoma of the breast)、腦癌(brain cancer)、腦膜瘤(meningioma)、神經膠質瘤(glioma)、星狀細胞瘤(astrocytoma)、寡樹突神經膠細胞瘤(oligodendroglioma)、神經管胚細胞瘤(medulloblastoma)、支氣管癌(bronchus cancer)、類癌瘤(carcinoid tumor)、子宮頸癌(cervical cancer)、子宮頸腺癌(cervical adenocarcinoma)、絨毛膜癌(choriocarcinoma)、脊索瘤(chordoma)、顱咽管瘤(craniopharyngioma)、大腸直腸癌(colorectal cancer)、大腸癌(colon cancer)、直腸癌(rectal cancer)、大腸直腸腺癌(colorectal adenocarcinoma)、上皮細胞癌(epithelial carcinoma)、室管膜瘤(ependymoma)、內皮肉瘤(endotheliosarcoma)、卡波西氏肉瘤(Kaposi's sarcoma)、多特發性出血性肉瘤(multiple idiopathic hemorrhagic sarcoma)、子宮內膜癌(endometrial cancer)、子宮癌(uterine cancer)、子宮肉瘤(uterine sarcoma)、食道癌(esophageal cancer)、食道腺癌(adenocarcinoma of the esophagus)、巴雷特腺癌(Barrett’s adenocarinoma)、尤恩氏肉瘤(Ewing sarcoma)、眼癌(eye cancer)、眼內黑色素瘤(intraocular melanoma)、視網膜母細胞瘤(retinoblastoma)、熟悉嗜伊紅性白血球增高(familiar hypereosinophilia)、膽囊癌(gall bladder cancer)、胃癌(gastric cancer)、胃腺癌(stomach adenocarcinoma)、胃腸道間質瘤(gastrointestinal stromal tumor, GIST)、頭頸部癌(head and neck cancer)、頭頸部鱗狀細胞癌(head and neck squamous cell carcinoma)、口腔癌(oral cancer)、口腔鱗狀細胞癌(oral squamous cell carcinoma, OSCC)、咽喉癌(throat cancer)、喉癌(laryngeal cancer)、咽癌(pharyngeal cancer)、鼻咽癌(nasopharyngeal cancer)、口咽癌(oropharyngeal cancer)、血癌(hematopoietic cancer)、白血病(leukemia)、急性淋巴性白血病(acute lymphocytic leukemia, ALL)、急性骨髓性白血病(acute myelocytic leukemia, AML)、慢性骨髓性白血病(chronic myelocytic leukemia, CML)、慢性淋巴性白血病(chronic lymphocytic leukemia, CLL)、淋巴瘤(lymphoma)、霍奇金淋巴瘤(Hodgkin lymphoma, HL)、非霍奇金淋巴瘤(non-Hodgkin lymphoma, NHL)、濾泡性淋巴瘤(follicular lymphoma)、慢性淋巴性白血病/小淋巴性淋巴瘤(chronic lymphocytic leukemia/small lymphocytic lymphoma, CLL/SLL)、套細胞淋巴瘤(mantle cell lymphoma, MCL)、邊緣區B細胞淋巴瘤(marginal zone B-cell lymphoma)、粘膜相關淋巴組織淋巴瘤(mucosa-associated lymphoid tissue (MALT) lymphoma)、結邊緣區B細胞淋巴瘤(nodal marginal zone B-cell lymphoma)、脾邊緣區B細胞淋巴瘤(splenic marginal zone B-cell lymphoma)、原發性縱隔B細胞淋巴瘤(primary mediastinal B-cell lymphoma)、柏基特淋巴瘤(Burkitt lymphoma)、淋巴漿細胞淋巴瘤(lymphoplasmacytic lymphoma)、華氏巨球蛋白血症(Waldenström's macroglobulinemia)、毛細胞白血病(hairy cell leukemia, HCL)、免疫母細胞性大細胞淋巴瘤(immunoblastic large cell lymphoma)、前趨B淋巴母細胞淋巴瘤及原發性中樞神經系統淋巴瘤(precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma)、T細胞NHL (T-cell NHL)、前趨T淋巴母細胞淋巴瘤/白血病(precursor T-lymphoblastic lymphoma/leukemia)、周邊T細胞淋巴瘤(peripheral T-cell lymphoma, PTCL)、皮膚T細胞淋巴瘤(cutaneous T-cell lymphoma, CTCL)、蕈樣肉芽腫(mycosis fungiodes)、塞扎裡綜合徵(Sezary syndrome)、血管免疫母細胞T細胞淋巴瘤(angioimmunoblastic T-cell lymphoma)、結外天然殺手T細胞淋巴瘤(extranodal natural killer T-cell lymphoma)、腸病型T細胞淋巴瘤(enteropathy type T-cell lymphoma)、皮下脂膜炎樣T細胞淋巴瘤(subcutaneous panniculitis-like T-cell lymphoma)、間變性大細胞淋巴瘤(anaplastic large cell lymphoma)、上述白血病/淋巴瘤之混合性腫瘤、多發性骨髓瘤(multiple myeloma, MM)、重鏈病(heavy chain disease)、α-鏈病(alpha chain disease)、γ-鏈病(gamma chain disease) 、μ-鏈病(mu chain disease)、血管母細胞瘤(hemangioblastoma)、炎性肌纖維母腫瘤(inflammatory myofibroblastic tumors)、免疫細胞性澱粉樣變性(immunocytic amyloidosis)、腎臟癌(kidney cancer)、腎母細胞瘤(nephroblastoma)、腎細胞癌(renal cell carcinoma)、肝癌(liver cancer或hepatocellular cancer)、惡性肝癌(malignant hepatoma)、肺癌(lung cancer)、支氣管肺癌(bronchogenic carcinoma)、小細胞肺癌(small cell lung cancer, SCLC)、非小細胞肺癌(non-small cell lung cancer, NSCLC)、肺腺癌(adenocarcinoma of the lung)、平滑肌肉瘤(leiomyosarcoma, LMS)、肥大細胞增多症(mastocytosis)、系統性肥大細胞增多症(systemic mastocytosis)、骨髓增生異常綜合症(myelodysplastic syndrome, MDS)、間皮瘤(mesothelioma)、骨髓增殖性疾病(myeloproliferative disorder, MPD)、真性紅細胞增多症(polycythemia Vera, PV)、原發性血小板增多症(essential thrombocytosis, ET)、特發性骨髓性增生(agnogenic myeloid metaplasia, AMM)、骨髓纖維化(myelofibrosis, MF)、慢性特發性骨髓纖維化(chronic idiopathic myelofibrosis)、慢性粒細胞白血病(chronic myelocytic leukemia, CML)、慢性中性粒細胞白血病(chronic neutrophilic leukemia, CNL)、增多綜合症(hypereosinophilic syndrome, HES)、神經母細胞瘤(neuroblastoma)、神經纖維瘤(neurofibroma)、第1型或第2型神經纖維瘤病(neurofibromatosis (NF) type 1 or type 2)、許旺細胞瘤(schwannomatosis)、神經內分泌癌(neuroendocrine cancer)、胃腸胰神經內分泌腫瘤(gastroenteropancreatic neuroendoctrine tumor, GEP-NET)、類癌瘤(carcinoid tumor)、骨肉瘤(osteosarcoma)、卵巢癌(ovarian cancer)、囊腺癌(cystadenocarcinoma)、卵巢胚胎癌(ovarian embryonal carcinoma)、卵巢腺癌(ovarian adenocarcinoma)、乳突狀腺癌(papillary adenocarcinoma)、胰臟癌(pancreatic cancer)、胰臟腺癌(pancreatic andenocarcinoma)、導管內乳頭狀黏液瘤(intraductal papillary mucinous neoplasm, IPMN)、胰島細胞瘤(islet cell tumor)、陰莖癌(penile cancer)、陰莖和陰囊之佩吉特氏病(Paget’s disease of the penis and scrotum)、松果體瘤(pinealoma)、原始神經外胚層腫瘤(primitive neuroectodermal tumor, PNT)、前列腺癌(prostate cancer或prostate adenocarcinoma)、直腸癌(rectal cancer)、橫紋肌肉瘤(rhabdomyosarcoma)、唾液腺癌(salivary gland cancer)、皮膚癌(skin cancer)、鱗狀細胞癌(squamous cell carcinoma, SCC)、角化棘皮瘤(keratoacanthoma, KA)、黑色素瘤(melanoma)、基底細胞癌(basal cell carcinoma, BCC)、小腸癌(small bowel cancer)、闌尾癌(appendix cancer)、軟組織肉瘤(soft tissue sarcoma)、惡性纖維組織細胞瘤(malignant fibrous histiocytoma, MFH)、脂肪肉瘤(liposarcoma)、惡性神經鞘瘤(malignant peripheral nerve sheath tumor, MPNST)、軟骨肉瘤(chondrosarcoma)、纖維肉瘤(fibrosarcoma)、黏液肉瘤(myxosarcoma)、皮脂腺癌(sebaceous gland carcinoma)、汗腺癌(sweat gland carcinoma)、滑液膜瘤(synovioma)、睾丸癌(testicular cancer)、精原細胞瘤(seminoma)、睾丸胚胎癌(testicular embryonal carcinoma)、甲狀腺癌(thyroid cancer)、甲狀腺乳突狀癌(papillary carcinoma of the thyroid或papillary thyroid carcinoma, PTC)、甲狀腺髓樣癌(medullary thyroid cancer)、尿道癌(urethral cancer)、陰道癌和外陰癌(vaginal cancer and vulvar cancer)、 外陰之佩吉特氏病(Paget’s disease of the vulva)。在某些實施方式中,本發明之聚醣共軛物、免疫組合物及疫苗可用以治療腦癌、肺癌、乳癌、口腔癌、食道癌、胃癌、肝癌、膽管癌、胰腺癌、直腸癌、腎臟癌、骨癌、皮膚癌、子宮頸癌、卵巢癌及前列腺癌。
如同上述,一有效量之本發明聚醣共軛物、免疫組合物或疫苗可經由適當的路徑投予至有治療需要之個體體內。該個體(例如人類)可以是一罹患癌症、疑似罹患癌症或易於罹患癌症之個體。該有效量可有效引發對共軛物或組合物中聚醣結構具有專一性之免疫反應,或足以產生可抑制腫瘤生長及/或減少腫瘤大小的免疫反應,或有效延緩標的癌症發病或減少癌症發展風險。確切的投予劑量將依個體不同而有所差異,舉例來說,個體之種族、年齡及生理狀況、副作用或疾病的嚴重程度、特定的化合物種類及投藥方式等。特定劑量可一天投予3次、一天投予2次、一天投予1次、隔天投予、每三天投予1次、每週投予1次、每二週投予1次、每三週投予1次或每四週投予1次。可多次投予本發明聚醣共軛物、免疫組合物或疫苗(例如2次、3次、4次、5次、6次、7次、8次、9次、10次、11次、12次、13次、14次或更多次)。
對一體重為70公斤之成人而言,一有效量之本發明聚醣共軛物、免疫組合物或疫苗可包含每單位劑型之約0.0001毫克至約3000毫克、約0.0001毫克至約2000毫克、約0.0001毫克至約1000毫克、約0.001毫克至約1000毫克、約0.01毫克至約1000毫克、約0.1毫克至約1000毫克、約1毫克至約1000毫克、約1毫克至約100毫克、約10毫克至約1000毫克,或約100毫克至約1000毫克的組合物。
為產生特定的治療功效,可以口服或非口服方法投予本發明聚醣共軛物、免疫組合物或疫苗,可每天投予或一天投予一或多次之約每公斤個體體重0.001到100毫克、約每公斤個體體重0.01到50毫克;較佳是約每公斤個體體重0.1到40毫克;較佳是約每公斤個體體重0.5到30毫克,約每公斤個體體重0.01到10毫克,約每公斤個體體重0.1到10毫克;更佳是約每公斤個體體重1到25毫克的劑量。
當可想見,本揭示內容是以成人為例,用以例示性地闡述投予本發明聚醣共軛物、免疫組合物或疫苗的劑量範圍。醫療人員或本所屬領域習知技藝人士可自行換算投予至孩童或青少年的劑量範圍,該劑量範圍可以少於或等於投予至成人的劑量範圍。
本發明之聚醣共軛物、免疫組合物或疫苗可與一或多種其他的治療活性劑合併投予至個體體內。藉由合併投予來改善本發明聚醣共軛物、免疫組合物或疫苗的生物可用率(bioavailability)、減少及/或改變其生理代謝、抑制其排出及/或改變其於個體體內的分佈。當可想見,該種治療可對相同疾病產生特定的治療功效,及/或產生不同的治療功效。
可在投予本發明聚醣共軛物、免疫組合物或疫苗之前或之後投予一或多種其他的治療活性劑。一般來說,各試劑可以單劑投予及/或依照試劑的特性於特定時間點投予。合併治療中其他的治療活性劑可配製為單一組合物以同時投予,或是配製為不同組合物分次投予。合併治療時需考量本發明化合物與其他治療活性劑之相容性及/或能否產生特定的治療功效。可預期地,合併治療中其他治療活性劑的利用性不會超過其個別使用時之利用性。在某些情況下,其利用性會低於其個別使用時之利用性。
本發明聚醣共軛物、免疫組合物或疫苗可與一或多種其他藥劑合併使用;舉例來說,該些藥劑可以是抗癌藥劑,其係包含生物治療抗癌藥劑及化學治療藥劑。
生物治療抗癌藥劑包含,但不限於,干擾素(interferon,例如干擾素-α、干擾素-γ)、細胞素(cytokine,例如腫瘤壞死因子(tumor necrosis factor))、疫苗、造血生長激素(hematopoietic growth factor)、單株血清治療(monoclonal serotherapy)、免疫刺激(immunostimulant)及或免疫調節劑(immunodulatory agent,例如IL-1、2、4、6或12)、免疫細胞生長激素(immune cell growth factor,例如GM-CSF)及抗體(例如賀癌平(Herceptin, trastuzumab)、T-DM1、癌思停(AVASTIN, bevacizumab)、愛必妥(ERBITUX, cetuximab)、維克替比(Vectibix, panitumumab)、利妥昔(Rituxan, rituximab)、百克沙(Bexxar, tositumomab))。
化學治療藥劑包含,但不限於,抗雌性素(anti-estrogen,例如他莫昔芬(tamoxifen)、雷洛昔芬(raloxifene)及甲地孕酮(megestrol))、黃體釋素促效劑(LHRH agonist,例如戈舍瑞林(goscrclin)及醋酸亮丙瑞林(leuprolide))、抗雄性素(anti-androgen,例如氟他胺(flutamide)及比卡魯胺(bicalutamide))、光動力治療(photodynamic therapies,例如維替泊芬(vertoporfin, BPD-MA)、酞菁(phthalocyanine)、光敏劑Pc4 (photosensitizer Pc4)及去甲氧基竹紅菌素(demethoxy-hypocrellin A, 2BA-2-DMHA))、氮芥(nitrogen mustard,例如環磷醯胺(cyclophosphamide)、異環磷醯胺(ifosfamide)、氯乙環磷醯胺(trofosfamide)、苯丁酸氮芥(chlorambucil)、雌莫司汀(estramustine)及美法崙(melphalan))、亞硝基尿素(nitrosoureas,例如卡莫司汀(carmustine, BCNU)及洛莫司汀(lomustine, CCNU))、烷基磺酸(alkylsulphonate,例如白消安(busulfan)及蘇消安(treosulfan))、三氮烯(triazene,例如達卡巴嗪(dacarbazine)及替莫唑胺(temozolomide))、含鉑化合物(platinum containing compound,例如順鉑(cisplatin)、卡鉑(carboplatin)及奧沙利鉑(oxaliplatin))、長春花生物鹼(vinca alkaloid,例如長春新鹼(vincristine)、長春花鹼(vinblastine)、長春地辛(vindesine)及長春瑞濱(vinorelbine))、類紫杉醇(taxoid,例如紫杉醇(paclitaxel)或與奈米粒子白蛋白結合之紫杉醇(Abraxane)、與十二碳六烯酸結合之紫杉醇(DHA-paclitaxel, Taxoprexin)、與聚谷氨酸結合之紫杉醇(PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX)、腫瘤活化前趨藥物ANG1005(Angiopep-2 bound to three molecules of paclitaxel)、紫杉醇-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-1)及與葡萄糖結合之紫杉醇(例如依托泊苷(etoposide)、磷酸依托泊苷(etoposide phosphate)、替尼泊苷(teniposide)、托泊替康(topotecan)、9-氨基喜樹鹹(9-aminocamptothecin)、康托替康(camptoirinotecan)、伊立替康(irinotecan)、甲磺酸(crisnatol)及絲裂黴素C (mytomycin C))等紫杉醇等效物)、抗代謝藥物(anti-metabolite)、二氫葉酸還原酶抑制劑(DHFR inhibitor,例如氨甲喋呤(methotrexate)、二氯甲氨蝶呤(dichloromethotrexate)、三甲蝶呤(trimetrexate)及依達曲沙(edatrexate))、肌苷-5'-單磷酸去氫酶抑制劑(IMP dehydrogenase inhibitor,例如黴酚酸(mycophenolic acid)、噻唑呋林(tiazofurin)、利巴韋林(ribavirin)及EICAR))、核糖核苷酸還原酶抑制劑(ribonuclotide reductase inhibitor,例如羥基尿素(hydroxyurea)及去鐵胺(deferoxamine))、尿嘧啶相似物(uracil analog,例如5-氟尿嘧啶(5-fluorouracil, 5-FU)、氟尿苷(floxuridine)、去氧氟尿苷(doxifluridine)、雷替曲塞(ratitrexed)、替加氟尿嘧啶(tegafur-uracil)及卡培他濱(capecitabine))、胞嘧啶相似物(cytosine analog,例如阿糖胞苷(cytarabine, ara C或cytosine arabinoside)及氟達拉濱(fludarabine))、嘌呤相似物(purine analog,例如巰基嘌呤(mercaptopurine)及硫鳥嘌呤(Thioguanine))、維生素D3相似物(Vitamin D3 analog,例如EB 1089、CB 1093及KH 1060)、異戊二烯抑制劑(isoprenylation inhibitor,例如洛伐他汀(lovastatin))、多巴胺能神經毒素(dopaminergic neurotoxin,例如1-甲基-4-苯基吡啶離子(1-methyl-4-phenylpyridinium ion))、細胞週期抑制劑(例如星形孢菌素(staurosporine))、放線菌素(actinomycin,例如放線菌素D)、博萊黴素(bleomycin,例如博萊黴素A2、博萊黴素B2及培洛黴素(peplomycin))、蒽環類藥物(anthracycline,例如柔紅黴素(daunorubicin)、多柔比星(doxorubicin)、聚乙二醇化脂質體多柔比星(pegylated liposomal doxorubicin)、伊達比星(idarubicin)、表柔比星(epirubicin)、吡柔比星(pirarubicin)、佐柔比星(zorubicin)及米托蒽醌(mitoxantrone))、多重抗藥性抑制劑(MDR inhibitor,例如維拉帕米(verapamil))、鈣離子三磷酸腺苷酶抑制劑(Ca2+
ATPase inhibitor,例如毒胡蘿蔔素(thapsigargin))、伊馬替尼(imatinib)、沙利度胺(thalidomide)、來那度胺(lenalidomide)、酪胺酸激酶抑制劑(tyrosine kinase inhibitor,例如阿西替尼(axitinib, AG013736)、波舒(bosutinib, SKI-606)、尼布(cediranib, RECENTINTM, AZD2171)、達沙替尼(dasatinib, SPRYCEL®
, BMS-354825)、厄洛替尼(erlotinib, TARCEVA®
)、吉非替尼(gefitinib, IRESSA®
)、伊馬替尼(imatinib, Gleevec®
, CGP57148B, STI-571)、拉帕替尼(lapatinib, TYKERB®
, TYVERB®
)、來他替尼(lestaurtinib, CEP-701)、那替尼(neratinib, HKI-272)、尼洛(nilotinib, TASIGNA®
)、馬沙尼(semaxanib, semaxinib, SU5416)、舒尼替尼(sunitinib, SUTENT®
, SU11248)、托西尼布(toceranib, PALLADIA®
)、凡德他尼(vandetanib, ZACTIMA®
, ZD6474)、瓦他拉尼(vatalanib, PTK787, PTK/ZK)、曲妥珠單抗(trastuzumab, HERCEPTIN®
)、貝伐單抗(bevacizumab, AVASTIN®
)、利妥昔單抗(rituximab, RITUXAN®
)、西妥昔單抗(cetuximab, ERBITUX®
)、帕尼單抗(panitumumab, VECTIBIX®
)、蘭尼單抗(ranibizumab, Lucentis®
)、尼洛(nilotinib, TASIGNA®
)、索拉非尼(sorafenib, NEXAVAR®
)、依維莫司(everolimus, AFINITOR®
)、阿崙單抗(alemtuzumab, CAMPATH®
)、吉妥單抗(gemtuzumab ozogamicin, MYLOTARG®
)、西羅莫司(temsirolimus, TORISEL®
)、ENMD-2076、PCI-32765、AC220、多韋替尼乳酸鹽(dovitinib lactate, TKI258, CHIR-258)、BIBW 2992 (TOVOKTM)、SGX523、PF-04217903、PF-02341066、PF-299804、BMS-777607、ABT-869、MP470、BIBF 1120 (VARGATEF®
)、AP24534、JNJ-26483327、MGCD265、DCC-2036、BMS-690154、CEP-11981、替洛尼(tivozanib, AV-951)、OSI-930、MM-121、XL-184、XL-647、及/或XL228)、蛋白酶抑制劑(proteasome inhibitor,例如硼替佐米(bortezomib, Velcade))、哺乳類斥消靈標的蛋白抑制劑(mTOR inhibitor,例如雷帕黴素(rapamycin)、西羅莫司(temsirolimus, CCI-779)、依維莫司(everolimus, RAD-001)、雷帕黴素衍生物(ridaforolimus, AP23573, Ariad)、AZD8055 (AstraZeneca)、BEZ235 (Novartis)、BGT226 (Norvartis)、XL765 (Sanofi Aventis)、PF-4691502 (Pfizer)、GDC0980 (Genetech)、SF1126 (Semafoe)及OSI-027 (OSI))、奧利默森(oblimersen)、吉西他濱(gemcitabine)、洋紅黴素(carminomycin)、亞葉酸鈣(leucovorin)、培美曲塞(pemetrexed)、環磷醯胺(cyclophosphamide)、達卡巴嗪(dacarbazine)、甲基芐肼(procarbizine或procarbazine)、潑尼松龍(prednisolone)、地塞米松(dexamethasone)、喜樹鹼(campathecin)、普卡黴素(plicamycin)、天門冬醯胺酶(asparaginase)、氨基蝶呤(aminopterin)、甲氨蝶呤(methopterin)、紫菜黴素(porfiromycin)、美法崙(melphalan)、異長春鹼(leurosidine)、環氧長春鹼(leurosine)、苯丁酸氮芥(chlorambucil)、曲貝替定(trabectedin)、海綿內酯(discodermolide)、洋紅黴素(carminomycin)及六甲基三聚氰胺(hexamethyl melamine)。
以本發明聚醣共軛物、免疫組合物或疫苗治療之個體是一哺乳動物,例如人類或牲畜(例如狗、貓、牛、豬、馬、綿羊或山羊)。該個體亦可是一非人類的基因轉殖動物,例如基因轉殖小鼠或基因轉殖豬。
實施例
下文提出多個實驗例來說明本發明的某些態樣,以利本發明所屬技術領域中具有通常知識者實作本發明,且不應將這些實驗例視為對本發明範圍的限制。據信習知技藝者在閱讀了此處提出的說明後,可在不需過度解讀的情形下,完整利用並實踐本發明。此處所引用的所有公開文獻,其全文皆視為本說明書的一部分。
實施例
1
:合成
GH-
乳糖
(GH-Lac)
衍生物
流程圖1闡述了合成GH-乳糖衍生物2-6
之方法。酵素:GalK:半乳糖激酶(galactokinase)、AtUSP:UDP-糖焦磷酸化酶(UDP-sugar pyrophosphorylase)、LgtC:α1,4-半乳糖苷基-轉移酶(α1,4-galactosyl- transferase)、PK:丙酮酸激酶(pyruvate kinase)、PPA:無機焦磷酸酶(inorganic pyrophosphatase)、GlmU:N
-乙醯葡萄糖胺-1-磷酸尿苷醯轉移酶(N
-acetyl glucosamine-1-phosphate uridyltransferase)、NahK:N
-乙醯己糖胺酶(N
-acetylhexosamine kinase)、LgtD:β1,3-N
-乙醯半乳糖胺轉移酶(β1,3-N
-acetylgalactosaminyltransferase)、FKP:雙功能之海藻糖酶/GDP-L-海藻糖焦磷酸化酶(bifunctional fucokinase/GDP-L- fucose pyrophosphorylase)、FutC:α-1,2-海藻糖轉移酶(α-1,2-fucosyltransferase)。流程圖1
依據已知方法由乳糖衍生物11-15
合成GH-乳糖衍生物2-6
(還原端衍生物) (流程圖1)。以半乳糖、α1,4-半乳糖苷基-轉移酶(LgtC)及UDP-Gal再生系統來合成Gb3-乳糖衍生物16-20
,其中該UDP-Gal再生系統包含UDP-糖焦磷酸化酶(AtUSP)、半乳糖激酶(GalK)、丙酮酸激酶(PK)及無機焦磷酸酶(PPA)。已知LgtC可用以合成α-(1→4)-半乳糖化衍生物。在本實驗中, LgtC亦具有良好活性以製備乳糖衍生物(11-15
)。Gb3-F16
、Gb3-苯基NO2 19
及Gb3-NO2 20
的產率分別為92、81及95 %,而Gb3-N3 17
及Gb3-苯基18
的產率則分別為67及69%。
利用Gb3-乳糖衍生物16-20
作為受子(acceptor),利用半乳糖胺、β1,3-N
-乙醯半乳糖胺轉移酶(LgtD)及UDP-GalNac再生系統來合成Gb4衍生物21-25
,其中該 UDP-GalNac再生系統包含N
-乙醯己糖胺酶(NahK)、N
-乙醯葡萄糖胺-1-磷酸尿苷醯轉移酶(GlmU)、丙酮酸激酶(PK)及無機焦磷酸酶(PPA)。經過量表現並分析確認後,利用LgtD來糖基化受子Gb3-F16
、Gb3-N3 17
及Gb3-苯基18
,以得到產率分別為90、87及89%的Gb4-F21
、Gb4-N3 22
及Gb4-苯基23
。由Gb3-苯基NO2 19
及Gb3-NO2 20
得到產率分別為72及61%的Gb4-苯基NO2 24
及Gb4-NO2 25
。
以β1,3-N
-乙醯半乳糖胺轉移酶(LgtD)及UDP-gal再生系統由Gb4衍生物21-25
及半乳糖得到Gb5-乳糖衍生物26-30
。Gb5-F26
、GB5-N3 27
、Gb5-苯基28
、Gb5-苯基NO2 29
及Gb5 NO2 30
的產率約為55%到79%。
以α-1,2-海藻糖轉移酶(FutC)、雙功能之海藻糖酶/GDP-L-海藻糖焦磷酸化酶(FKP)、無機焦磷酸酶(PPA)、丙酮酸激酶(PK)及海藻糖由Gb5-乳糖衍生物26-30
來合成GH-乳糖衍生物2-6
。以受子Gb5-F26
及Gb5-苯基28
來得到產率分別為75及93%的GH-F2
及GH-苯基4
。利用受子Gb5-N3 27
、Gb5-苯基NO2 29
及Gb5-NO2 30
來得到產率分別為49、65及66%的GH-N3 3
、GH-苯基NO2 5
及GH-NO2 6
。
實施例
2
:合成
GH-
海藻糖
(GH-Fuc)
衍生物
流程圖2闡述以化學酵素合成GH-海藻糖衍生物的方法。反應條件:FKP、Fut C、PPA、PK、Mg2+
、ATP、GTP。流程圖2
結合海藻糖衍生物及受子Gb5寡醣,並以重組FKP、α-1,2-海藻糖轉移酶(FutC)、PPA及PK來合成GH-海藻糖衍生物7-10
(非還原端衍生物) (流程圖2)。先以化學方法合成起始材料-具有戊胺31
的Gb5寡醣。再以化學酵素方法得到產率約為43%到83%的GH-海藻糖衍生物7-10
。即使化合物36
會與FKP進行反應以產生GDP-36
,其仍舊非為一適當的FutC供體(donor),且僅能產生極微量的產物。此外,化合物37
非為FKP的受質,且不會產生GDP-37
中間產物。
利用核磁共振光譜(nuclear magnetic resonance (NMR) spectroscopy)及高解析質譜(high-resolution mass spectrometry, HRMS)來分析各經純化之GH衍生物及其截斷形式的化學結構。
實施例
3
:合成
GH
衍生物
-DT
共軛物
流程圖3闡述合成以GH-乳糖及GH-海藻糖修飾之疫苗的方法。流程圖3
為合成GH-乳糖及GH-海藻糖之DT-共軛物(1-DT至10-DT),將胺端的GH-乳糖衍生物2-6
或GH-海藻糖衍生物7-10
與同雙功能之對硝基苯基(p
-nitrophenyl)連結子反應,以高產率地提供相對應之半酯。以逆相層析法純化後,於生理食鹽水緩衝液(pH 7.8)中結合半酯及DT,反應至隔日(流程圖3)。以基質輔助雷射脫附游離飛行時間質譜法(MALDI-TOF MS)來分析結合至DT之GH衍生物的數量。表1闡述了MALDI-TOF分析平均醣結合之結果。a
波峰m/z
。 表1
實施例4:合成GH-乳糖及GH-海藻糖衍生物的前趨物
依據與有效糖核苷酸再生結合的酵素方法,以糖甘轉移酶(LgtC, LgtD, Futc)及輔因子再生系統(UDP-Gal, UDP-GalNAc, GDP-Fuc)來製備GH-乳糖及GH-海藻糖衍生物。以化學方法合成起始乳糖衍生物11-15
及海藻糖衍生物32-37
(流程圖4-8)。
流程圖4:合成乳糖結構單元(11)
流程圖4
以已知方法合成化合物S1
。於0°C的環境中,將咪唑(imidazole, 208毫克, 3.07 mmol)加入包含S1 (630毫克, 1.02 mmol)之DMF (30 mL)溶液中,並加入291微升(1.13 mmol)之叔丁基(氯)二苯基矽烷(tert-Butyl(chloro)diphenylsilane)。將反應混合物緩慢加熱至室溫。連續攪拌13個小時以濃縮反應溶液。將殘基溶於0°C的砒啶(pyridine, 20毫升),並加入乙酐(acetic anhydride, 401微升, 3.93 mmol)。將反應混合物緩慢加熱至室溫。連續攪拌10小時後,於0°C緩慢加入甲醇(1毫升)以中止反應,於減壓環境中移除揮發性物質。利用乙酸乙酯(80毫升)萃取殘基,以飽和之NaHCO3
溶液洗滌,再以Na2
SO4
乾燥後,過濾並濃縮產物。以快速矽膠層析(flsash silica get chromatography,溶於己烷之0-40% EtOAc)進行純化,以製得S2
(667毫克,64%)。1
H NMR (600 MHz, CDCl3
) δ 7.78 - 7.71 (m, 4H)、7.46 - 7.25 (m, 11H)、5.43 (s, 1H)、5.23 - 5.15 (m, 2H)、4.95 (m, 1H)、4.87 - 4.81 (m, 2H)、4.42 (d,J
= 8.0 Hz, 1H)、4.32 - 4.30 (dd,J
= 1.4, 12.5 Hz, 1H)、4.25 (d,J
= 3.6 Hz, 1H)、4.14 (t,J
= 9.6 Hz, 1H)、4.07 (d,J
= 1.5, 12.5 Hz, 1H)、3.96 - 3.90 (m, 2H)、3.85 - 3.81 (m, 1H)、3.44 - 3.40 (m, 1H)、3.31 - 3.30 (m, 2H)、3.08 (m, 2H)、2.08 - 2.00 (m, 9H)、1.77 (s, 3H)、 1.60 - 1.58 (m, 2H)、1.48 - 1.45 (m, 2H)、1.41 (s, 9H)、1.35 - 1.33 (m, 2H)、1.05 (s, 9H)。13
C NMR (150 MHz, CDCl3
) δ 170.69、170.66、169.83、168.64、155.99、137.55、136.02、135.43、133.50、132.20、129.95、129.92、129.20、128.26、127.93、127.67、126.54、101.40、100.60、100.26、75.23、74.26、73.36、72.36、72.21、71.68、69.22、68.99、68.62、66.27、61.12、29.77、29.08、28.44、26.84、23.30、20.90、20.82、20.80、20.59、19.45。以HRMS (ESI-TOF, MNa+
)計算得C53
H71
NO17
SiNa+
1044.4383,可得1044.4404。
於0°C 的環境中,將AcOH (246微升, 4.10 mmol)加入包含S2
(425毫克, 0.41 mmol)的THF溶液中。加入4.1毫升(4.10 mmol)之溶於THF且濃度為1.0 M的四丁基氟化銨(tetrabutylammonium fluoride)溶液。將反應混合物緩慢加熱至室溫。連續攪拌7小時後,於減壓環境下濃縮反應溶液。利用乙酸乙酯(70毫升)萃取殘基,以飽和之NaHCO3
溶液洗滌,再以Na2
SO4
乾燥後,過濾並濃縮產物。以快速管柱層析(column chromatography,溶於己烷之50-80% EtOAc)進行純化,以製得S3
(279毫升,87 %)。1
H NMR (600 MHz, CDCl3
) δ 7.47 - 7.42 (m, 2H)、7.40 - 7.32 (m, 3H)、5.44 (s, 1H)、5.26 - 5.15 (m, 2H)、4.92 - 4.83 (m, 2H)、4.57 (m, 2H)、4.45 (d,J
= 8.0 Hz, 1H)、4.31 - 4.23 (m, 2H)、4.01 (dd,J
= 12.4, 1.5 Hz, 1H)、3.90 (m, 2H)、3.83 - 3.74 (m, 2H)、3.48 - 3.44 (m, 2H)、3.37 (d,J
= 9.7 Hz, 1H)、3.06 (m, 2H)、2.01 (dd,J
= 6.4, 2.8 Hz, 12H)、1.56 - 1.54 (m, 2H),1.48 - 1.30 (m, 13H)。13
C NMR (150 MHz、CDCl3
) δ 170.94、170.60、169.88、169.05、156.21、137.74、129.37、128.44、126.72、101.54、101.14、100.86、79.35、75.30、74.68、73.49、72.64、72.31、71.84、70.11、69.40、68.78、66.47、60.46、40.63、29.78、29.20、28.63、23.21、21.06、20.95。以HRMS (ESI-TOF, MNa+
)計算得C37
H53
NO17
Na+
806.3206,可得806.3212。
於0°C 的環境中,將130微升(1.2 mmol)之2,6-二甲基吡啶(2,6-lutidine)加入包含S3
(221毫克,0.28 mmol)之乾DCM (10毫升)溶液中。加入150微升(1.2 mmol)之二乙胺基三氟化硫(Diethylaminosulfur trifluoride)。以超音波振盪8小時,再真空濃度產物。以快速矽膠管柱層析(溶於己烷之10-50% EtOAc) 進行純化,以得到S4
(129毫克,59%)。1
H NMR (600 MHz, CDCl3
) δ 7.47 - 7.39 (m, 2H)、7.39 - 7.32 (m, 3H)、5.45 (s, 1H)、5.28 - 5.18 (m, 2H)、4.92 - 4.85 (m, 2H)、4.72 - 4.55 (m, 2H)、4.55 - 4.41 (m, 2H)、4.32 - 4.24 (m, 2H)、4.02 (dd,J
= 12.4, 1.4 Hz, 1H)、3.90 - 3.80 (m, 2H)、3.51 - 3.41 (m, 3H)、3.07 (dd,J
= 12.9, 6.4 Hz, 2H)、2.01 (dd,J
= 5.9, 4.3 Hz, 12H)、1.58 - 1.51 (m, 2H)、1.51 - 1.38 (m, 11H)、1.38 - 1.26 (m, 2H)。19
F NMR (470 MHz, CDCl3
) δ -234.24 (td,J
= 47.2, 29.6 Hz)。13
C NMR (150 MHz、CDCl3
) δ 170.97、170.43、169.85、169.06、156.16、137.62、129.41、128.45、126.68、101.49、100.99、100.92、81.51、80.36、79.28、74.67、74.64、74.03、73.90、73.39、72.72、72.21、71.71、69.99、69.32、68.68、66.59、40.63、29.86、29.18、28.62、23.32、21.08、20.94。以HRMS (ESI-TOF, MNa+
)計算得C37
H52
FNO16
Na+
808.3162,可得808.3185。
將NaOMe (5毫克)加入包含S4
(105毫克,0.13 mmol)的甲醇(10毫升)溶液中。加入Amberlite IR-120中和反應溶液後,過濾並濃縮產物。以5毫升之溶於水的90% TFA處理殘基。連續攪拌2小時後,以逆相管柱層析法(RP-18)濃縮並純化反應溶液,據此製得乳糖衍生物11
(49毫克,89%)。5-胺戊基β-D-吡喃半乳糖-(1→4)-6-去氧-6-氟-β-D- 葡萄糖呱喃醣苷(化合物11
) (5-aminopentyl β-D-galactopyranosyl-(1→4) -6-deoxy-6-fluoro-β-D-glucopyranoside (Compound11
))
1
H NMR (600 MHz, D2
O) δ 4.88-4.71 (m, 1H)、4.54 (d,J
= 8.0 Hz, 1H)、4.46 (d,J
= 7.8 Hz, 1H)、3.93 - 3.90 (m, 2H)、3.84 - 3.65 (m, 8H)、3.56 (dd,J
= 10.0, 7.8 Hz, 1H)、3.34 (dd,J
= 9.3, 8.1 Hz, 1H)、3.02 (t,J
= 7.5 Hz, 2H)、1.75 - 1.65 (m, 4H)、1.51 - 1.43 (m, 2H).19
F NMR (471 MHz, D2
O) δ -234.79 (td,J
= 47.8, 31.6 Hz)。13
C NMR (150 MHz、D2
O) δ 105.60、104.84、84.54、83.43、79.71、79.67、78.00、76.88、75.96、75.84、75.42、75.14、73.56、72.90、71.19、63.71、41.98、30.82、29.05、24.73。以HRMS (ESI-TOF,MH+
)計算得C17
H32
FNO10
H+
430.2083,可得430.2092。
流程圖5:合成乳糖結構單元(12
) 流程圖5
於0°C 的環境中,將4-甲苯磺醯氯(4-toluenesulfonyl chloride,0.8克,4.23 mmol)加入包含S1
(1.9克,3.51 mmol)之砒啶溶液(30毫升)中。將反應混合物緩慢加熱至室溫。連續攪拌8小時後,以快速管柱層析濃縮並純化反應溶液(溶於DCM之2-8%甲醇),以製得S5
(1.2克,45%);1
H NMR (600 MHz, CDCl3
) δ 7.78 - 7.76 (d,J
= 8.0 Hz, 2H)、7.44 - 7.42 (m, 2H)、7.34 (m, 3H)、7.24 - 7.23 (d,J
= 8.0 Hz, 2H)、5.49 (s, 1H)、4.61 (m, 1H)、4.52 (d,J
= 10.3 Hz, 1H)、4.38 (d,J
= 7.9 Hz, 1H)、4.28 - 4.17 (m, 2H)、4.15 (d,J
= 3.5 Hz, 1H)、4.02 - 4.00 (m, 1H)、3.77 - 3.72 (m, 2H)、3.61 - 3.55 (m, 4H)、3.49 - 3.41 (m, 3H)、3.32 (m, 1H)、2.38 (s, 3H)、1.58 - 1.55 (m, 2H)、1.47 - 1.44 (m, 2H)、1.40 (s, 9H)、1.36 - 1.33 (m, 2H)。13
C NMR (150 MHz、CDCl3
) δ 156.26、137.72、132.87、130.03、129.45、128.52、128.24、126.63、102.79、102.46、101.49、79.29、77.76、75.35、74.77、73.44、72.77、72.61、70.33、70.11、69.47、69.05、67.14、40.61、29.85、29.25、28.64、23.38、21.82。利用HRMS (ESI-TOF, MNa+
)計算得C36
H51
NO15
SNa+
792.2872,可得792.2798。
於110°C的環境中,將疊氮化鈉(sodium azide,169毫克,2.60 mmol)加入包含S5
(204毫克,0.26 mmol)之DMF溶液(5毫升)中。連續攪拌14小時後,以快速管柱層析濃縮並純化反應溶液(溶於DCM之2-8%甲醇),以製得S6
(148毫克,89%)。1
H NMR (600 MHz, CDCl3
) δ 7.44 (m, 2H)、7.33 - 7.31 (m, 3H)、5.46 (s, 1H)、4.29 - 4.24 (m, 2H)、4.20 (d,J
= 12.5 Hz, 1H)、4.04 (m Hz, 1H)、3.97 (d,J
= 12.2 Hz, 1H)、3.84 (m, 1H)、3.72 - 3.63 (m, 1H)、3.60 - 3.33 (m, 10H)、3.26 (s, 1H)、3.04 (m, 2H)、1.59 - 1.57 (m, 2H)、1.45 - 1.19 (m, 13H)。13
C NMR (150 MHz、CDCl3
) δ 137.57、129.45、128.47、126.48、103.37、102.58、101.42、79.91、79.34、75.46、74.62、74.53、73.47、72.58、70.47、69.96、69.12、67.05、51.17、40.43、29.73、29.24、28.56、23.33。以HRMS (ESI-TOF, MNa+
)計算得C29
H44
N4
O12
Na+
663.2848,可得663.2859。
以5毫升之溶於水的90% TFA處理S6 (122毫克),並攪拌2小時,以逆相管柱層析(RP-18)濃縮及純化產物,以製得乳糖衍生物12
(80毫克,93%)。5-胺戊基β-D-吡喃半乳糖-(1→4)-6-疊氮基-6-去氧-β-D-葡萄糖呱喃醣苷(化合物12
) (5-aminopentyl β-D-galactopyranosyl-(1→4) -6-azido-6-deoxy-β-D-glucopyranoside (Compound12
))
1
H NMR (600 MHz, D2
O) δ 4.54 (d,J
= 8.1 Hz, 1H)、4.44 (d,J
= 7.8 Hz, 1H)、3.98 - 3.91 (m, 2H)、3.85 - 3.60 (m, 10H)、3.55 (dd,J
= 9.9, 7.8 Hz, 1H)、3.38 - 3.32 (m, 1H)、3.06 - 2.99 (m, 2H)、1.76 - 1.65 (m, 4H)、1.52 - 1.43 (m, 2H)。13
C NMR (150 MHz、D2
O) δ 105.84、104.76、82.08、78.14、76.98、76.40、75.54、75.25、73.64、72.93、71.26、63.76、53.14、42.09、30.92、29.13、24.83。以HRMS (ESI-TOF, MH+
)計算得C17
H32
N4
O10
H+
453.2191,可得453.2201。
流程圖6:合成乳糖結構單元(13
)
流程圖6
於0°C 的環境中,將25微升(0.27 mmol)之酚及70毫克(0.27 mmol)之三苯基磷(triphenylphosphine)加入包含S3
(190毫克,0.24 mmol)之乾DCM溶液(10毫升)中。加入38微升(0.27 mmol)之偶氮二甲酸二乙酯(Diethyl azodicarboxylate)。以超音波振盪4小時,再真空濃縮產物。以快速矽膠管柱層析(溶於己烷之10-50%)純化殘基,以製得S7
(138毫克,67%)。1
H NMR (600 MHz, CDCl3
) δ 7.43 - 7.42 (dd,J
= 7.7, 1.7 Hz, 2H)、7.36 - 7.31 (m, 3H)、7.31 - 7.26 (m, 2H)、6.98 - 6.90 (m, 3H)、5.42 (s, 1H)、5.26 - 5.17 (m, 2H)、4.94 (dd,J
= 9.7, 8.0 Hz, 1H)、4.67 (dd,J
= 10.3, 3.7 Hz, 1H)、4.49 - 4.44 (m, 3H)、4.26 - 4.23 (m, 3H)、4.17 (m, 1H)、4.06 - 3.96 (m, 2H)、3.80 (dt,J
= 9.7, 6.3 Hz, 1H)、3.66 (m, 1H)、3.43 (dt,J
= 9.6, 6.6 Hz, 1H)、3.34 (s, 1H)、3.05 (d,J
= 6.2 Hz, 2H)、2.01 (s, 3H)、2.00 (s, 3H)、1.97 (s, 3H)、1.88 (s, 3H)、1.59 - 1.48 (m, 2H)、1.48 - 1.38 (m, 11H)、1.36 - 1.19 (m, 2H)。13
C NMR (150 MHz、CDCl3
) δ 170.89、170.56、169.88、168.91、158.56、156.15、137.67、129.82、129.37、128.42、126.67、121.71、115.00、101.49、101.01、100.79、79.23、75.35、74.07、73.28、72.80、72.36、71.83、69.83、69.26、68.68、66.51、65.92、40.63、29.81、29.17、28.62、23.28、21.02、20.94、20.93、20.84。以HRMS (ESI-TOF, MNa+
)計算得C43
H57
NO17
Na+
882.3519,可得882.3542。
將NaOMe (3毫克)加入包含S7
(110毫克,0.12 mmol)之甲醇溶液(5毫升)中,再攪拌6小時。以Amberlite IR-120中和反應溶液後,進行過濾及濃縮。以5毫升之溶於水的90% TFA處理殘基。攪拌2小時後,以逆相管柱層析(RP-18)濃縮及純化反應溶液,以製得乳糖衍生物13
(45毫克,78%)。5-胺戊基β-D-吡喃半乳糖-(1→4)-6-O-苯基-β-D-葡萄糖呱喃醣苷(化合物13
) (5-aminopentyl β-D-galactopyranosyl-(1→4) -6-O-phenyl-β-D-glucopyranoside (Compound13
))
1
H NMR (600 MHz, D2
O) δ 7.42 (dd,J
= 8.7, 7.4 Hz, 2H)、7.12 - 7.07 (m, 3H)、4.55 (d,J
= 8.0 Hz, 1H)、4.46 (dd,J
= 11.1, 1.6 Hz, 1H)、4.37 (dd,J
= 11.1, 4.0 Hz, 1H)、4.30 (d,J
= 7.8 Hz, 1H)、3.96 - 3.87 (m, 3H)、3.84 (d,J
= 3.4 Hz, 1H)、3.79 - 3.67 (m, 4H)、3.56 (dd,J
= 4.0, 8.3 Hz, 1H)、3.52 (m, 1H)、3.45 - 3.35 (m, 2H)、3.02 (t,J
= 7.5 Hz, 2H)、1.73 - 1.63 (m, 4H)、1.50 - 1.41 (m, 2H)。13
C NMR (150 MHz、CDCl3
) δ 163.11、135.23、135.21、127.09、120.35、108.11、107.54、82.71、80.68、79.65、78.32、78.17、77.73、76.06、75.44、73.81、71.22、66.35、44.62、33.46、31.66、27.34。利用HRMS (ESI-TOF, MH+
)計算得C23
H37
NO11
H+
504.2439,可得504.2450。
流程圖7:合成乳糖結構單元(14
)
流程圖7
於室溫中,將42毫克(0.30 mmol)之4-硝基苯酚(4-nitrophenol)及81毫克(0.30 mmol)之三苯基磷加入包含S3
(220毫克,0.28 mmol)之乾DCM溶液(10毫升)中。加入43微升(0.30 mmol)之偶氮二甲酸二乙酯。以超音波振盪5小時,再真空濃縮產物。以快速矽膠管柱層析(溶於己烷之20-60% EtOAc) 純化殘基,以製得S8
(235毫克,92%)。1
H NMR (600 MHz, CDCl3
) δ 8.19 (d,J
= 8.9 Hz, 2H)、7.41 (d,J
= 6.2 Hz, 2H)、7.33 (m, 3H)、7.00 (d,J
= 8.9 Hz, 2H)、5.43 (s, 1H)、5.23 - 5.19 (m, 2H)、4.90 (t,J
= 8.8 Hz, 1H)、4.76 (dd,J
= 10.3, 2.7 Hz, 1H)、4.52 (s, 1H)、4.47 (d,J
= 7.7 Hz, 2H)、4.36 (d,J
= 10.4 Hz, 1H)、4.26 - 4.24 (m, 3H)、4.04 - 3.93 (m, 2H)、3.78 - 3.73 (m, 2H)、3.41 (m, 2H)、3.03 (d,J
= 5.5 Hz, 2H)、2.05 - 1.94 (m, 9H)、1.87 (s, 3H)、1.56 - 1.35 (m, 13H)、1.29 - 1.91 (m, 2H)。13
C NMR (150 MHz、CDCl3
) δ 170.72、170.26、169.73、168.72、163.43、156.06、142.12、137.53、129.30、128.33、126.53、126.13、114.89、101.33、100.93、100.61、79.13、77.43、75.31、73.60、73.18、72.54、72.00、71.72、69.99、69.34、68.53、66.71、66.56、40.50、29.75、29.06、28.52、23.16、20.89、20.82、20.81、20.80。利用HRMS (ESI-TOF, MNa+
)計算得C43
H56
N2
O19
Na+
927.3369,可得927.3377。
將NaOMe (3毫克)加入包含S8
(155毫克,0.17 mmol) 之甲醇溶液(5毫升)中,再攪拌6小時。以Amberlite IR-120中和反應溶液後,進行過濾及濃縮。以5毫升之溶於水的90% TFA處理殘基。攪拌2小時後,以逆相管柱層析(RP-18)濃縮及純化反應溶液,以製得乳糖衍生物14
(78毫克,83%)。5-胺戊基β-D-吡喃半乳糖-(1→4)-6-O-對硝基苯基-β-D-葡萄糖呱喃醣苷(化合物14
) (5-aminopentyl β-D-galactopyranosyl-(1→4) -6-O-p
-nitrophenyl-β-D-glucopyranoside (Compound14
))
1
H NMR (600 MHz, D2
O) δ 8.29 (d,J
= 9.3 Hz, 2H)、7.20 (d,J
= 9.3 Hz, 2H)、4.57 - 4.53 (m, 3H)、4.32 (d,J
= 7.7 Hz, 1H)、3.97 - 3.84 (m, 4H)、3.84 - 3.66 (m, 4H)、3.60 (dt,J
= 11.7, 5.8 Hz, 1H)、3.53 (dd,J
= 9.9, 7.7 Hz, 1H)、3.47 (dd,J
= 9.9, 3.4 Hz, 1H)、3.41 - 3.35 (m, 1H)、2.97 (t,J
= 7.5 Hz, 2H)、1.69 - 1.63 (m, 4H)、1.45 - 1.41 (m, 2H)。13
C NMR (150 MHz、D2
O) δ 163.56、141.49、126.22、115.08、103.07、102.25、77.72、75.43、74.34、72.85、72.78、72.45、70.74、70.16、68.47、66.40、61.03、39.34、28.17、26.48、22.07。以HRMS (ESI-TOF, MH+
)計算得C23
H36
N2
O13
H+
549.2290,可得549.2294。
流程圖8:合成乳糖結構單元(15
)
流程圖8
於110°C的環境中,將碘化鈉(363毫克,2.40 mmol)加入包含S3
(188毫克,0.24 mmol)之DMF溶液(5毫升)中。攪拌14小時後,以快速管柱層析濃縮並純化反應溶液(溶於DCM之2-8%甲醇),以製得S9
(146毫克,84%)。1
H NMR (600 MHz, MeOD) δ 7.52 - 7.46 (m, 2H)、7.30 - 7.28 (m, 3H)、5.58 (s, 1H)、4.48 - 4.43 (m, 1H)、4.27 (dd,J
= 7.8, 4.0 Hz, 1H)、4.20 - 4.09 (m, 3H)、3.89 - 3.78 (m, 2H)、3.66 - 3.49 (m, 5H)、3.42 - 3.13 (m, 4H)、3.00 (t,J
= 7.0 Hz, 2H)、1.69 - 1.55 (m, 2H)、1.49 - 1.28 (m, 13H)。13
C NMR (150 MHz、MeOD) δ 157.17、138.13、128.51、127.64、126.08、103.78、102.62、100.81、83.24、78.43、75.91、74.32、73.84、73.45、72.09、70.48、69.57、68.78、66.92、46.63、39.93、29.27、29.05、27.44、22.94。以HRMS (ESI-TOF, MNa+
)計算得C29H44INO12Na+
748.1800,可得748.1758。
將亞硝酸鈉(124毫克,1.80 mmol) 加入包含S9
(133毫克,0.18 mmol)之DMF溶液(5毫升)中,於室溫反應2天。以快速管柱層析濃縮並純化反應溶液(溶於DCM之2-8%甲醇),以製得S10
(40毫克,35%)。1
H NMR (600 MHz, MeOD) δ 7.45 (dt,J
= 4.3, 2.3 Hz, 2H)、7.27 - 7.25 (m, 3H)、5.55 (s, 1H)、5.12 (dd,J
= 13.6, 2.5 Hz, 1H)、4.59 - 4.44 (m, 6H)、4.36 (d,J
= 7.5 Hz, 1H)、4.23 (d,J
= 7.8 Hz, 1H)、4.14 - 4.07 (m, 4H)、3.67 - 3.49 (m, 5H)、3.48 - 3.39 (m, 2H)、3.18 - 3.14 (m, 1H)、2.93 (t,J
= 7.0 Hz, 2H)、1.56 - 1.45 (m, 2H)、1.39 - 1.32 (m, 11H)、1.32 - 1.24 (m, 2H)。13
C NMR (150 MHz、MeOD) δ 157.20、138.17、128.56、127.69、126.10、103.60、102.87、100.86、79.81、78.45、75.91、75.74、74.62、73.23、72.10、71.38、70.17、69.68、68.78、67.01、39.91、29.25、29.02、27.44、22.90。以HRMS (ESI-TOF, MNa+
)計算得C29
H44
N2
O14
Na+
667.2685,可得667.2726。
以5毫升之溶於水的90% TFA處理S10
(40毫克,0.06 mmol ) ,並攪拌2小時,以逆相管柱層析(RP-18)濃縮及純化產物,以製得乳糖衍生物15
(22毫克,78%)5-胺戊基β-D-吡喃半乳糖-(1→4)-6-去氧-6-硝基-β-D-葡萄糖呱喃醣苷(化合物15
) (5-aminopentyl β-D-galactopyranosyl-(1→4)-6-deoxy-6-nitro-β-D-glucopyranoside (Compound15
))
1
H NMR (600 MHz, D2
O) δ 4.56 (d,J
= 8.1 Hz, 1H)、4.47 (d,J
= 7.8 Hz, 1H)、4.34 (d,J
= 9.5 Hz, 1H)、3.95 (d,J
= 3.3 Hz, 1H)、3.86 - 3.65 (m, 8H)、3.57 (dd,J
= 9.9, 7.9 Hz, 1H)、3.35 (t,J
= 8.6 Hz, 1H)、3.04 - 2.97 (m, 2H)、1.66 (m, 4H)、1.47 - 1.38 (m, 2H)。13
C NMR (150 MHz、D2
O) δ 105.84、104.88、82.22、78.46、78.25、76.89、75.36、75.24、73.91、73.53、73.37、71.21、63.71、42.06、30.93、29.09、24.76。以HRMS (ESI-TOF, MH+
)計算得C17
H32
N2
O12
H+
457.2028,可得457.2036。
利用已知方法合成化合物33
、34
、35
、36
及37
。
合成
Gb3-
乳糖衍生物
在15毫升離心管中加入5.0毫升之包含乳糖衍生物(10-15毫克)、半乳糖(1.0等量)、PEP (4.4等量)、ATP二納鹽(0.1等量)、UTP二納鹽(0.1等量)、MgCl2
(10 mM)、α1,4-半乳糖苷基-轉移酶(LgtC,3.0單位)、半乳糖激酶(GalK, 2.0單位)、UDP-糖焦磷酸化酶(AtUSP,2.8單位)、丙酮酸激酶(PK,2.5單位)及無機焦磷酸酶(PPA,2.5單位)的Tris-HCl緩衝液(100 mM, pH 7.0)以進行反應。將反應混合物置於室溫,並以300 rmp的轉速作用至隔日。以5:3:2正丁醇/乙酸/水作為顯影溶劑,並將培養盤以溶於乙醇之大茴香醛(anisaldehyde)進行染色,以TLC分析觀測結果。將離心管置於熱水浴槽(80°C)作用10分鐘,離心(10000 rpm,15分鐘)後真空濃縮其上清液。以C-18膠層析純化液態殘基,再以濃度梯度沖提液(由100% 水到溶於水之80%甲醇)來進行沖提。僅收集包含產物之分液,冷凍乾燥後,以NMR光譜儀及HRMS來分析所得產物。
合成
Gb4-
乳糖衍生物
在15毫升離心管中加入3.0毫升之包含Gb3衍生物(8-12毫克)、N
-乙醯半乳糖胺(N
-acetylgalactosamine,GAlNAc,1.1等量)、PEP (4.4等量)、ATP二納鹽(0.1等量)、UTP二納鹽(0.1等量)、MgCl2
(10 mM)、β1,3-N
-乙醯半乳糖胺轉移酶(β1,3GalNAcT,LgtD,3.5單位)、N-
乙醯己糖胺酶(NahK,5.0單位)、N-
乙醯葡萄糖胺-1-磷酸尿苷醯轉移酶(GlmU,3.0單位)、PK (2.5單位)及PPA (2.5單位)的Tris-HCl緩衝液(100 mM, pH 7.0) 以進行反應。將反應混合物置於室溫,並以300 rmp的轉速作用至隔日。以5:3:2正丁醇/乙酸/水作為顯影溶劑,並將培養盤以溶於乙醇之大茴香醛進行染色,以TLC分析觀測結果。將離心管置於熱水浴槽(80°C)作用10分鐘,離心(10000 rpm,15分鐘)後真空濃縮其上清液。以C-18膠層析純化液態殘基,再以濃度梯度沖提液(由100% 水到溶於水之80%甲醇)來進行沖提。僅收集包含產物之分液,冷凍乾燥後,以NMR光譜儀及HRMS來分析所得產物。
合成
Gb5-
乳糖衍生物
在15毫升離心管中加入3.0毫升之包含Gb4衍生物(5-8毫克)、半乳糖(1.1等量)、PEP (4.4等量)、ATP二納鹽(0.1等量)、UTP二納鹽(0.1等量)、MgCl2
(10 mM)、β-1,3-N
-乙醯半乳糖胺轉移酶(β1,3GalT,LgtD,5.0單位)、GalK (2.5單位)、 AtUSP (4.0單位)、PK (2.5單位)及PPA (2.5單位)的Tris-HCl緩衝液(100 mM, pH 7.0) 以進行反應。將反應混合物置於室溫,並以300 rmp的轉速作用至隔日。以3:2:2正丁醇/乙酸/水作為顯影溶劑,並將培養盤以溶於乙醇之大茴香醛進行染色,以TLC分析觀測結果。將離心管置於熱水浴槽(80°C)作用10分鐘,離心(10000 rpm,15分鐘)後真空濃縮其上清液。以C-18膠層析純化液態殘基,再以濃度梯度沖提液(由100% 水到溶於水之70%甲醇)來進行沖提。僅收集包含產物之分液,冷凍乾燥後,以NMR光譜儀及HRMS來分析所得產物。
合成
Globo H-
乳糖衍生物或
Globo H-
海藻糖衍生物
在15毫升離心管中加入3.0毫升之包含Gb5衍生物(4-6毫克)、L-海藻糖或其衍生物(1.2等量)、PEP (4.4等量)、ATP二納鹽(0.1等量)、GTP二納鹽(0.1等量)、MgCl2
(10 mM)、α-1,2-海藻糖轉移酶(FutC,3.0單位)、雙功能之海藻糖酶/GDP-L-海藻糖焦磷酸化酶(FKP)、PK (2.5單位)及PPA (2.5單位)的Tris-HCl緩衝液(100 mM, pH 7.0) 以進行反應。將反應混合物置於室溫,並以300 rmp的轉速作用至隔日。以3:2:2正丁醇/乙酸/水作為顯影溶劑,並將培養盤以溶於乙醇之大茴香醛進行染色,以TLC分析觀測結果。將離心管置於熱水浴槽(80°C)作用10分鐘,離心(10000 rpm,15分鐘)後真空濃縮其上清液。以C-18膠層析純化液態殘基,再以濃度梯度沖提液(由100% 水到溶於水之80%甲醇)來進行沖提。僅收集包含產物之分液,冷凍乾燥後,以NMR光譜儀及HRMS來分析所得產物。5-胺戊基α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-去氧-6-氟-β-D-葡萄糖呱喃醣苷(化合物16
) (5-aminopentyl α-D-Galactopyranosyl-(1→4) -β-D-galactopyranosyl-(1→4)-6-deoxy- 6-fluoro-β-D-glucopyranoside (Compound16
))
1
H NMR (600 MHz, D2
O) δ 4.97 (d,J
= 3.9 Hz, 1H)、4.94 - 4.70 (m, 1H)、4.53 (d,J
= 8.0 Hz, 1H)、4.53 (d,J
= 7.7 Hz, 1H)、4.37 (t,J
= 6.5 Hz, 1H)、4.05 (dd,J
= 7.9, 3.2 Hz, 2H)、3.98 - 3.64 (m, 14H)、3.60 (dd,J
= 10.3, 7.8 Hz, 1H)、3.33 (dd,J
= 9.3, 8.1 Hz, 1H)、2.92 (m,2H)、1.76 - 1.64 (m, 4H)、1.52 - 1.42 (m, 2H)。19
F NMR (470 MHz、CDCl3
) δ -234.92 (td、J
= 47.0、32.9 Hz)。13
C NMR (150 MHz、D2
O) δ 103.29、102.15、100.31、81.94、80.82、77.40、77.36、75.40、74.29、73.35、73.23、72.87、72.15、70.87、70.81、70.25、69.13、68.92、68.53、60.49、60.38、39.37、28.17、26.55、22.07。以HRMS (ESI-TOF, MH+
)計算得C23
H42
FNO15
H+
592.2611,可得592.2620。5-胺戊基α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-疊氮基-6-去氧-β-D-葡萄糖呱喃醣苷(化合物17
) (5-aminopentyl α-D-Galactopyranosyl-(1→4) -β-D-galactopyranosyl-(1→4)-6-azido- 6-deoxy-β-D-glucopyranoside (Compound17
))
1
H NMR (600 MHz, D2
O) δ 4.97 (d,J
= 3.9 Hz, 1H)、4.55 (d,J
= 8.0 Hz, 1H)、4.49 (d,J
= 7.8 Hz, 1H)、4.37 (t,J
= 6.6 Hz, 1H)、4.06 (dd,J
= 7.6, 3.0 Hz, 2H)、4.00 - 3.56 (m, 16H)、3.34 (t,J
= 8.6 Hz, 1H)、3.01 - 2.94 (t,J
= 7.2 Hz, 2H)、1.72 - 1.66 (m, 4H)、1.49 - 1.43 (m, 2H)。13
C NMR (150 MHz、D2
O) δ 106.16、104.71、103.03、82.33、80.03、78.20、77.04、76.44、75.62、74.89、73.61、73.55、72.99、71.87、71.66、71.28、63.23、63.10、53.12、42.21、30.97、29.78、24.88。以HRMS (ESI-TOF, MH+
)計算得C23
H42
N4
O15
H+
615.2719,可得615.2734。5-胺戊基α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-O-苯基-β-D-葡萄糖呱喃醣苷(化合物18
) (5-aminopentyl α-D-Galactopyranosyl-(1→4) -β-D- galactopyranosyl-(1→4)-6-O- phenyl-β-D-glucopyranoside (Compound18
))
1
H NMR (600 MHz, D2
O) δ 7.43 (t,J
= 8.0 Hz, 2H)、7.11 (m, 3H)、4.94 (d,J
= 3.9 Hz, 1H)、4.56 (d,J
= 8.0 Hz, 1H)、4.48 (d,J
= 10.3 Hz, 1H)、4.42 (dd,J
= 10.9, 3.5 Hz, 1H)、4.35 (m, 2H)、4.04 (d,J
= 3.0 Hz, 1H)、3.97 - 3.81 (m, 8H)、3.79 - 3.65 (m, 4H)、3.65 - 3.48 (m, 3H)、3.37 (t,J
= 8.3 Hz, 1H)、2.98 (t,J
= 6.7 Hz, 2H)、1.68 (s, 4H)、1.47 (dd,J
= 14.6, 7.4 Hz, 2H)。13
C NMR (150 MHz、D2
O) δ 160.54、132.68、124.56、117.82、105.93、104.97、103.00、80.47、80.05、78.23、77.13、75.83、75.73、74.84、73.54、73.43、72.92、71.85、71.65、71.26、68.62、63.23、63.15、42.12、30.93、29.34、24.81。以 HRMS (ESI-TOF, MH+
)計算得C29
H47
NO16
H+
666.2968,可得666.2979。5-胺戊基α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-O-對硝基苯基-β-D-葡萄糖呱喃醣苷(化合物19
) (5-aminopentyl α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-O-p
-nitrophenyl-β-D- glucopyranoside (Compound19
))
1
H NMR (600 MHz, D2
O) δ 8.29 (d,J
= 9.3 Hz, 2H)、7.20 (d,J
= 9.3 Hz, 2H)、4.94(d,J
= 4.0 Hz, 1H)、4.59 - 4.50 (m, 3H)、4.37 (d,J
= 7.7 Hz, 1H)、4.34(t,J
= 5.7 Hz, 1H)、4.04 (d,J
= 2.8 Hz, 1H)、3.99 (d,J
= 2.7 Hz, 1H)、3.97 - 3.84 (m, 4H)、3.84 - 3.66 (m, 4H)、3.73 - 3.66 (m, 5H)、3.60 - 3.53 (m, 2H)、3.39 - 3.36 (m, 1H)、, 2.97 (t,J
= 7.5 Hz, 2H)、1.68 - 1.63 (m, 4H)、1.46 - 1.41 (m, 2H)。13
C NMR (150 MHz、D2
O) δ 166.28、144.25、128.97、117.83、106.20、104.97、102.99、80.82、79.96、78.25、77.13、75.68、75.56、74.86、73.54、73.43、72.93、71.85、71.65、71.25、69.09、63.22、63.12、42.15、30.94、29.56、24.84。以HRMS (ESI-TOF, MH+
)計算得C29
H46
N2
O18
H+
711.2818,可得711.2800。5-胺戊基α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-去氧-6-硝基-β-D-葡萄糖呱喃醣苷(化合物20
) (5-aminopentyl α-D-Galactopyranosyl-(1→4)- β-D-galactopyranosyl-(1→4)-6-deoxy -6-nitro-β-D-glucopyranoside (Compound20
))
1
H NMR (600 MHz, D2
O) δ 4.96 (d,J
= 3.9 Hz, 1H)、4.54 (m, 2H)、4.36 (t,J
= 6.2 Hz, 1H)、4.31 (d,J
= 9.2 Hz, 1H)、4.05 - 4.03 (m, 2H)、3.99 - 3.51 (m, 15H)、3.32 (m, 1H)、3.00 (m, 2H)、1.68 - 1.60 (m, 4H)、1.46 - 1.40 (m, 2H)。13
C NMR (150 MHz、D2
O) δ 102.70、101.73、100.04、79.37、76.98、75.20、73.91、72.59、71.80、70.45、70.40、70.34、69.95、68.86、68.61、68.32、65.87、60.19、60.13、 52.12、39.71、29.10、28.16、22.00。利用HRMS (ESI-TOF, MH+
)計算得C23
H42
N2
O17
H+
619.2556,可得619.2559。5-胺戊基2-乙醯胺基-2-去氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-去氧-6-氟-β-D-葡萄糖呱喃醣苷(化合物21
) (5-aminopentyl 2-acetamido-2-deoxy-β-D- galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-deoxy-6-fluoro-β-D-glucopyranoside (Compound21
))
1
H NMR (600 MHz, D2
O) δ 4.93 (d,J
=3.9 Hz, 1H)、4.92-4.74 (m, 2H)、4.75 (d,J
= 10.5 Hz, 1H)、4.66 (d,J
= 8.3 Hz, 1H)、4.55 (d,J
= 8.0 Hz, 1H)、4.53 (d,J
= 7.8 Hz, 1H)、4.41 (t,J
= 6.5 Hz, 1H)、4.28 (d,J
= 2.5 Hz, 1H)、4.07 (d,J
= 3.1 Hz, 1H)、4.02 - 3.64 (m, 18H)、3.62 (dd,J
= 10.2, 7.8 Hz, 1H)、3.34 (m, 1H)、2.99 (t,J
= 7.5 Hz, 2H)、2.07 (s, 3H)、1.75 - 1.64 (m, 4H)、1.55 - 1.43 (m, 2H)。19
F NMR (471 MHz、D2
O) δ -234.84 (td、J
= 47.0、32.9 Hz).13
C NMR (150 MHz、D2
O) δ 177.91、106.06、105.95、104.89、103.15、84.69、83.57、81.42、80.22、80.18、79.97、78.16、77.68、77.05、76.10、75.98、75.65、74.85、73.59、73.52、73.03、71.67、70.50、70.35、63.74、63.11、63.07、55.35、42.19、30.95、29.68、24.99、24.85。以HRMS (ESI-TOF, MH+
)計算得C31
H55
FN2
O20
H+
795.3405,可得795.3429。5-胺戊基2-乙醯胺基-2-去氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-疊氮基-6-去氧-β-D-葡萄糖呱喃醣苷(化合物22
) (5-aminopentyl 2-acetamido-2-deoxy-β-D- galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-azido-6-deoxy-β-D-glucopyranoside (Compound22
))
1
H NMR (600 MHz, D2
O) δ 4.94 (d,J
= 3.9 Hz, 1H)、4.66 (d,J
= 8.4 Hz, 1H)、4.56 (d,J
= 8.0 Hz, 1H)、4.51 (d,J
= 7.8 Hz, 1H)、4.40 (t,J
= 6.6 Hz, 1H)、4.28 (d,J
= 2.6 Hz, 1H)、4.07 (d,J
= 3.1 Hz, 1H)、4.02 - 3.57 (m, 22H)、3.35 (t,J
= 8.5 Hz, 1H)、2.99 (t,J
= 7.5 Hz, 2H)、2.07 (s, 3H)、1.76 - 1.63 (m, 4H)、1.48 (dt,J
= 15.5, 7.7 Hz, 2H)。13
C NMR (150 MHz、D2
O) δ 177.91、106.19、105.95、104.72、103.13、82.41、81.43、79.90、78.23、77.68、77.07、76.44、75.66、74.85、73.59、73.53、73.00、72.99、71.67、70.50、70.34、63.74、63.11、63.05、55.36、53.13、42.17、30.97、29.57、24.99、24.88。以HRMS (ESI-TOF, MH+
)計算得C31
H55
N5
O20
H+
818.3513,可得818.3543。5-胺戊基2-乙醯胺基-2-去氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-O-苯基-β-D-葡萄糖呱喃醣苷(化合物23
) (5-aminopentyl 2-acetamido-2-deoxy-β-D- galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-O-phenyl-β-D-glucopyranoside (Compound 23))
1
H NMR (600 MHz, D2
O) δ 7.40 (t,J
= 7.8 Hz, 2H)、7.08 (m, 3H)、4.89 (d,J
= 3.8 Hz, 1H)、4.64 (d,J
= 8.4 Hz, 1H)、4.54 (d,J
= 7.9 Hz, 1H)、4.47 - 4.31 (m, 4H)、4.25 (d,J
= 2.3 Hz, 1H)、4.00 - 3.84 (m, 9H)、3.84 - 3.67 (m, 9H)、3.67 - 3.45 (m, 3H)、3.43 - 3.34 (m, 1H)、2.98 (m, 2H)、2.05 (s, 3H)、1.66 (m, 4H)、1.44 (m, 2H)。13
C NMR (150 MHz、D2
O) δ 177.92、160.53、132.66、124.54、117.79、105.96、105.95、104.96、103.10、81.41、80.58、79.91、78.24、77.67、77.15、75.83、75.77、75.58、74.80、73.52、73.40、72.99、72.90、71.67、70.50、70.33、68.64、63.74、63.10、55.34、42.06、30.92、29.13、25.00、24.80。利用HRMS (ESI-TOF, MH+
)計算得C37
H60
N2
O21
H+
869.3761,可得869.3795。5-胺戊基2-乙醯胺基-2-去氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-O-對硝基苯基-β-D-葡萄糖呱喃醣苷(化合物24
) (5-aminopentyl 2-acetamido-2-deoxy-β- D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-O-p
-nitrophenyl-β-D-glucopyranoside (Compound24
))
1
H NMR (600 MHz, D2
O) δ 8.29 (d,J
= 9.1 Hz, 2H)、7.20 (d,J
= 9.2 Hz, 2H)、4.90 (d,J
= 3.8 Hz, 1H)、4.65 (d,J
= 8.4 Hz, 1H)、4.56 (m, 3H)、4.41 - 4.33 (m, 2H)、4.25 (d,J
= 2.6 Hz, 1H)、4.02 - 3.74 (m, 13H)、3.73 - 3.63 (m, 7H)、3.61 - 3.52 (m, 2H)、3.38 (t,J
= 8.7 Hz, 1H)、2.87 (t,J
= 7.3 Hz, 2H)、2.06 (s, 3H)、1.66 - 1.59 (m, 4H)、1.44 - 1.40 (m, 2H)。13
C NMR (150 MHz、D2
O) δ 177.90、166.28、144.25、128.97、117.83、106.20、105.93、104.97、103.10、81.39、80.92、79.85、78.27、77.68、77.16、75.72、75.57、74.83、73.52、73.42、73.00、72.89、71.66、70.50、70.32、69.11、63.74、63.10、55.36、42.08、30.94、29.20、24.99、24.82。利用HRMS (ESI-TOF, MH+
)計算得C37
H59
N3
O23
H+
914.3612,可得914.3609。5-胺戊基2-乙醯胺基-2-去氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-去氧-6-硝基-β-D-葡萄糖呱喃醣苷(化合物25
) (5-aminopentyl 2-acetamido-2-deoxy-β- D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-deoxy-6-nitro-β-D-glucopyranoside (Compound25
))
1
H NMR (600 MHz, D2
O) δ 4.96 - 4.90 (m, 1H)、4.68 - 4.50 (m, 4H)、4.39 (t,J
= 6.1 Hz, 1H)、4.32 (d,J
= 9.4 Hz, 1H)、4.27 (d,J
= 2.0 Hz, 1H)、4.05 (dd,J
= 9.6, 2.9 Hz, 1H)、4.01 - 3.64 (m, 19H)、3.64 - 3.53 (m, 1H)、3.38 - 3.29 (m, 1H)、3.07 - 2.91 (m, 2H)、2.05 (s, 3H)、1.70 - 1.60 (m, 4H)、1.47 - 1.40 (m, 2H)。13
C NMR (150 Hz、D2
O) δ 175.16、103.45、103.22、102.10、100.37、79.82、78.70、77.08、75.53、74.92、74.24、72.71、72.08、71.09、70.77、70.75、70.60、70.25、68.91、67.74、67.58、60.98、60.35、60.24、52.59、39.31、39.29、28.18、26.37、22.23、22.01。以HRMS (ESI-TOF, MH+
)計算得C31
H55
N3
O22
H+
822.3350,可得822.3357。5-胺戊基β-D-吡喃半乳糖-(1→3)-2-乙醯胺基-2-去氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-去氧-6-氟-β-D-葡萄糖呱喃醣苷(化合物26
) (5-aminopentyl β-D-galactopyranosyl-(1→3)- 2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-deoxy-6-fluoro-β-D-glucopyranoside (Compound26
))
1
H NMR (600 MHz, D2
O) δ 4.97 - 4.84 (m, 2H)、4.71 (d,J
= 8.5 Hz, 1H)、4.54 (d,J
= 8.0 Hz, 1H)、4.51 (d,J
= 7.8 Hz, 1H)、4.46 (d,J
= 7.8 Hz, 1H)、4.40 (t,J
= 6.4 Hz, 1H)、4.26 (d,J
= 2.7 Hz, 1H)、4.19 (d,J
= 3.0 Hz, 1H)、4.11 - 4.03 (m, 2H)、3.95 (m, 6H)、3.91 - 3.50 (m, 18H)、3.33 (t,J
= 8.7 Hz, 1H)、2.98 (m, 2H)、2.04 (s, 3H)、1.70-1.67 (m, 4H)、1.54 - 1.33 (m, 2H)。19
F NMR (471 MHz、D2
O) δ -234.85 (td、J
= 47.0、28.2 Hz)。13
C NMR (150 MHz、D2
O) δ 175.11、104.79、103.31、102.89、102.13、100.38、81.92、80.80、79.55、78.63、77.45、77.41、77.19、75.40、74.98、74.59、74.29、73.34、73.22、72.89、72.43、72.08、72.03、70.82、70.57、70.28、70.25、68.90、68.55、67.97、67.58、62.45、60.98、60.94、60.34、60.31、51.48、39.43、28.19、26.91、22.25、22.09。HRMS (ESI-TOF, MH+
)計算得C37
H65
FN2
O25
H+
957.3933,可得957.3969。5-胺戊基β-D-吡喃半乳糖-(1→3)-2-乙醯胺基-2-去氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-疊氮基-6-去氧-β-D-葡萄糖呱喃醣苷(化合物27
) 5-aminopentyl (β-D-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-azido-6-deoxy-β-D-glucopyranoside (Compound27
))
1
H NMR (600 MHz, D2
O) δ 4.94 (d,J
= 3.7 Hz, 1H)、4.72 (d,J
= 8.6 Hz, 1H)、4.56 (d,J
= 8.0 Hz, 1H)、4.52 (d,J
= 7.8 Hz, 1H)、4.48 (d,J
= 7.8 Hz, 1H)、4.40 (t,J
= 6.4 Hz, 1H)、4.28 (d,J
= 2.0 Hz, 1H)、4.21 (d,J
= 2.8 Hz, 1H)、4.16 - 4.04 (m, 2H)、4.04 - 3.89 (m, 7H)、3.89 - 3.51 (m, 19H)、3.35 (t,J
= 8.5 Hz, 1H)、3.02 (t,J
= 7.6 Hz, 2H)、2.05 (s, 3H)、1.79 - 1.68 (m, 4H)、1.49 - 1.47 (m, 2H)。13
C NMR (150 MHz、CDCl3
) δ 180.40、110.09、108.73、108.18、107.26、105.66、84.95、84.85、83.94、82.43、80.76、80.27、79.89、79.61、78.98、78.20、77.73、77.38、76.13、75.87、75.55、75.50、74.20、73.85、73.26、72.87、66.28、66.23、65.64、65.59、56.78、55.67、44.64、33.48、31.75、27.55、27.39。利用HRMS (ESI-TOF, MH+
)計算得C37
H65
N5
O25
H+
980.4041,可得980.4080。5-胺戊基β-D-吡喃半乳糖-(1→3)-2-乙醯胺基-2-去氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-O-苯基-β-D-葡萄糖呱喃醣苷(化合物28
) (5-aminopentyl β-D-galactopyranosyl-(1→3)- 2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-O-phenyl-β-D-glucopyranoside (Compound28
))
1
H NMR (600 MHz, D2
O) δ 7.43 (t,J
= 7.2 Hz, 2H)、7.11 (d,J
= 8.2 Hz, 3H)、4.91 (d,J
= 3.5 Hz, 1H)、4.71 (t,J
= 8.3 Hz, 1H)、4.56 (t,J
= 7.6 Hz, 1H)、4.48 - 4.36 (m, 5H)、4.26 (s, 1H)、4.20 (a, 1H)、4.09 (t,J
= 10.1 Hz, 1H)、3.98 - 3.63 (m, 22H)、3.59 - 3.51 (m, 3H)、3.39 (t,J
= 8.3 Hz, 1H)、2.91 (m, 2H)、2.05 (s, 3H)、1.67 (m, 4H)、1.45 (m, 2H)。13
C NMR (150 MHz、D2
O) δ 177.87、160.55、132.68、124.57、117.82、107.55、105.96、105.64、104.97、103.10、82.31、81.37、80.57、79.91、78.24、77.74、77.34、77.15、75.83、75.77、75.20、74.79、73.40、73.33、73.00、71.66、71.31、70.72、70.32、68.65、65.21、63.74、63.69、63.10、54.23、42.28、31.01、30.15、25.01、24.87。以HRMS (ESI-TOF, MH+
)計算得C43 H70 N2 O26 +H: 1031.4290,可得1031.4300。5-胺戊基β-D-吡喃半乳糖-(1→3)-2-乙醯胺基-2-去氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-O-對硝基苯基-β-D-葡萄糖呱喃醣苷(化合物29
) (5-aminopentyl β-D-galactopyranosyl-(1→3)- 2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-O-p
-nitrophenyl-β-D-glucopyranoside (Compound29
))
1
H NMR (600 MHz, D2
O) δ 8.30 (d,J
= 9.3 Hz, 2H)、7.20 (d,J
= 9.3 Hz, 2H)、4.91 (d,J
= 3.6 Hz, 1H)、4.71 (d,J
= 8.5 Hz, 1H)、4.57 (d,J
= 5.8 Hz, 3H)、4.47 (d,J
= 7.7 Hz, 1H)、4.41 - 4.33 (m, 2H)、4.26 (s, 1H)、4.20 (d,J
= 2.6 Hz, 1H)、4.00 (m, 1H)、3.93 - 3.62 (m, 21H)、3.59 - 3.53 (m, 3H)、3.38 (t,J
= 8.8 Hz, 2H)、2.88 (t,J
= 7.3 Hz, 2H)、2.04 (s, 3H)、1.58 (m, 4H)、1.42 - 1.25 (m, 2H)。13
C NMR (150 MHz、D2
O) δ 175.10、163.52、141.49、126.21、115.07、104.80、103.47、102.87、102.22、100.34、79.55、78.60、78.15、77.07、75.52、74.98、74.59、74.39、72.97、72.81、72.44、72.06、70.65、70.57、70.24、70.20、68.90、68.55、67.97、67.56、66.35、60.98、60.94、60.33、51.49、39.41、28.21、26.92、22.26、22.10。利用HRMS (ESI-TOF, MH+
)計算得C43
H69
N3
O28
H+
1076.4140,可得1076.4135。5-胺戊基β-D-吡喃半乳糖-(1→3)-2-乙醯胺基-2-去氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-去氧-6-硝基-β-D-葡萄糖呱喃醣苷(化合物30
) (5-aminopentyl β-D-galactopyranosyl-(1→3)- 2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-deoxy-6-nitro-β-D-glucopyranoside (Compound30
))
1
H NMR (600 MHz, D2
O) δ 4.93 (d,J
= 6.9 Hz, 1H)、4.70 (t,J
= 9.1 Hz, 1H)、4.60 - 4.51 (m, 2H)、4.47 (d,J
= 7.8 Hz, 1H)、4.43 - 4.28 (m, 2H)、4.27 (d,J
= 2.4 Hz, 1H)、4.20 (d,J
= 2.6 Hz, 1H)、4.17 (d,J
= 2.5 Hz, 1H)、4.07 - 3.97 (m, 3H)、3.97 - 3.49 (m, 22H)、3.41 - 3.28 (m, 1H)、3.01 (t,J
= 7.2 Hz, 2H)、2.04 (s, 3H)、1.86 - 1.55 (m, 4H)、1.63 - 1.25 (m, 3H)。13
C NMR (150 MHz、D2
O) δ 175.10、104.79、103.45、102.91、102.09、100.36、79.83、79.54、78.67、77.06、75.53、74.98、74.59、74.24、72.71、72.43、72.08、71.15、71.09、70.78、70.61、70.57、70.26、68.89、68.54、67.96、67.58、60.97、60.93、60.34、60.23、51.47、39.29、28.19、26.35、22.26、22.01。以HRMS (ESI-TOF, MH+
)計算得C37
H65
N3
O27
H+
984.3878,可得984.3864。5-胺戊基α-L-吡喃海藻糖-(1→2)-β-D-吡喃半乳糖-(1→3)-2-乙醯胺基-2-去氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)- 6-去氧-6-氟-β-D-葡萄糖呱喃醣苷(化合物2
) (5-aminopentyl α-L-fucopyranosyl-(1→2)- β-D-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)- 6-deoxy-6-fluoro-β-D-glucopyranoside (Compound2
))
1
H NMR (600 MHz, D2
O) δ 5.25 (d,J
= 2.6 Hz, 1H)、4.92 (d,J
= 3.7 Hz, 2H)、4.84-4.74 (m, 1H)、4.65 (d,J
= 7.6 Hz, 1H)、4.56 (d,J
= 7.6 Hz, 1H)、4.55 (d,J
= 9.8 Hz, 1H)、4.52 (d,J
= 7.7 Hz, 1H)、4.41 (t,J
= 6.5 Hz, 1H)、4.28 (m, 2H)、4.07 (d,J
= 3.1 Hz, 1H)、4.13 - 3.64 (m, 32H)、3.34 (t,J
= 8.5 Hz, 1H)、2.99 (t,J
= 7.5 Hz, 2H)、2.07 (s, 3H)、1.75 - 1.64 (m, 4H)、1.55 - 1.43 (m, 2H)。19
F NMR (470 MHz、CDCl3
) δ -234.87 (td、J
= 47.0、32.9 Hz).13
C NMR (150 MHz、D2
O) δ 174.28、103.95、103.33、102.15、102.04、100.45、99.27、81.94、81.72、80.83、78.23、77.49、77.46、77.21、76.36、76.11、75.46、75.07、74.63、74.31、73.58、73.36、73.24、72.91、72.10、71.85、70.83、70.29、70.16、69.52、69.18、69.11、68.48、68.02、67.83、66.79、60.98、60.96、60.36、51.65、39.43、28.21、26.84、22.25、22.10、15.31。利用HRMS (ESI-TOF, MH+
)計算得C43
H75
FN2
O29
H+
1103.4512,可得1103.4549。5-胺戊基α-L-吡喃海藻糖-(1→2)-β-D-吡喃半乳糖-(1→3)-2-乙醯胺基-2-去氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-疊氮基-6-去氧-β-D-葡萄糖呱喃醣苷(化合物3
) (5-aminopentyl α-L-fucopyranosyl-(1→2)- β-D-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-6-azido-6-deoxy-β-D-glucopyranoside (Compound3
))
1
H NMR (600 MHz, D2
O) δ 5.26 (d,J
= 4.1 Hz, 1H)、4.92 (d,J
= 4.0 Hz, 1H)、4.64 (d,J
= 7.7 Hz, 1H)、4.57 (d,J
= 7.8 Hz, 1H)、4.55 (d,J
= 8.1 Hz, 1H) , 4.50 (d,J
= 7.7 Hz, 1H)、4.41 (t,J
= 6.6 Hz, 1H)、4.34 - 4.23 (m, 2H)、4.13 (d,J
= 2.5 Hz, 1H)、4.09 - 3.57 (m, 31H)、3.35 (t,J
= 8.5 Hz, 1H)、3.06 - 2.99 (m, 2H)、2.07 (s, 3H)、1.77 - 1.63 (m, 4H)、1.53 - 1.41 (m, 2H)、1.24 (d,J
= 6.6 Hz, 3H)。13
C NMR (150 MHz、D2
O) δ 177.02、106.70、106.20、104.79、104.72、103.18、102.02、82.42、80.99、79.88、79.11、78.85、78.27、77.81、77.37、77.07、76.44、76.33、75.66、74.84、74.59、73.57、72.96、72.89、72.26、71.91、71.85、71.22、70.77、70.56、69.53、63.73、63.70、63.10、54.39、53.13、42.09、30.94、29.17、24.99、24.85、18.05。以HRMS (ESI-TOF, MH+
)計算得C43
H75
N5
O29
H+
1126.4620,可得1126.4639。5-胺戊基α-L-吡喃海藻糖-(1→2)-β-D-吡喃半乳糖-(1→3)-2-乙醯胺基-2-去氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)- 6-O-苯基-β-D-葡萄糖呱喃醣苷(化合物4
) (5-aminopentyl α-L-fucopyranosyl-(1→2)- β-D-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)- 6-O-phenyl-β-D-glucopyranoside (Compound4
))
1
H NMR (600 MHz, D2
O) δ 7.43 (t,J
= 8.0 Hz, 2H)、7.11 (t,J
= 8.0 Hz, 3H)、5.26 (d,J
= 4.1 Hz, 1H)、4.89 (d,J
= 4.0 Hz, 1H)、4.64 (d,J
= 7.7 Hz, 1H)、4.57 (d,J
= 7.6 Hz, 1H)、4.55 (d,J
= 8.0 Hz, 1H)、4.48 (d,J
= 10.1 Hz, 1H)、4.45 - 4.34 (m, 3H)、4.27 - 4.24 (m, 2H)、4.13 (d,J
= 2.1 Hz, 1H)、4.06 - 3.62 (m, 27H)、3.58 - 3.50 (m, 2H)、3.39 (dd,J
= 9.3, 8.2 Hz, 1H)、2.91 (t,J
= 7.4 Hz, 2H)、2.07 (s, 3H)、1.73 - 1.60 (m, 4H)、1.51 - 1.39 (m, 2H)、1.24 (d,J
= 6.6 Hz, 3H)。13
C NMR (150 MHz、D2
O) δ 174.28、157.80、129.93、121.82、115.08、103.95、103.24、102.23、102.05、100.40、99.28、78.22、77.85、77.14、76.36、76.11、75.54、75.07、74.62、74.42、73.58、73.09、73.04、72.05、71.85、70.64、70.28、70.13、69.52、69.17、69.11、68.48、68.02、67.81、66.78、65.91、60.98、60.95、60.38、60.35、51.64、39.56、28.27、27.49、22.25、22.13、15.31。以HRMS (ESI-TOF, MH+
)計算得C49H80N2O30H+
1177.4869,可得1177.4918。5-胺戊基α-L-吡喃海藻糖-(1→2)-β-D-吡喃半乳糖-(1→3)-2-乙醯胺基-2-去氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)- 6-O-對硝基苯基-β-D-葡萄糖呱喃醣苷(化合物5
) (5-aminopentyl α-L-fucopyranosyl-(1→2)- β-D-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)- 6-O-p
-nitrophenyl-β-D-glucopyranoside (Compound5
))
1
H NMR (600 MHz, D2
O) δ 8.30 (d,J
= 8.8 Hz, 2H)、7.21 (d,J
= 8.8 Hz, 2H)、5.26 (d,J
= 4.1 Hz, 1H)、4.89 (d,J
= 3.6 Hz, 1H)、4.65 (d,J
= 7.6 Hz, 1H)、4.60 (m, 3H)、4.39 (m, 2H)、4.25 - 4.21 (m, 1H)、4.13 (s, 1H)、4.01- 3.65 (m, 28H)、3.59 - 3.56 (m, 3H)、3.45 - 3.35 (m, 1H)、2.94 (t,J
= 6.9 Hz, 2H)、2.07 (s, 3H)、1.66 - 1.62 (m, 4H)、1.44 - 1.42 (m, 2H)、1.24 (d,J
= 6.3 Hz, 3H)。13
C NMR (150 MHz、D2
O) δ 177.03、166.29、144.26、128.97、117.83、106.69、106.25、104.98、104.79、103.15、102.02、80.94、79.82、79.10、78.85、78.31、77.81、77.37、77.16、76.32、75.73、75.56、74.82、74.78、74.59、73.40、72.97、72.88、72.26、71.91、71.86、71.22、70.77、70.55、69.53、69.12、65.21、63.73、63.70、63.09、54.39、42.19、30.97、24.99、24.86、18.05。HRMS (ESI-TOF, MH+
)計算得C49
H79
N3
O32
H+
1222.4719,可得1222.4729。5-胺戊基 α-L-吡喃海藻糖-(1→2)-β-D-吡喃半乳糖-(1→3)-2-乙醯胺基-2-去氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-6-去氧-6-硝基-β-D-葡萄糖呱喃醣苷(化合物6
) (5-aminopentyl α-L-fucopyranosyl-(1→2)- β-D-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)- 6-deoxy-6-nitro-β-D-glucopyranoside (Compound6
))
1
H NMR (600 MHz, D2
O) δ 5.26 (s, 1H)、4.91 (s, 1H)、4.69 - 4.52 (m, 5H)、4.42 (d,J
= 6.4 Hz, 1H)、4.34 (d,J
= 7.5 Hz, 1H)、4.26 (m, 2H)、4.13 (s, 1H)、4.12 - 3.62 (m, 28H)、3.57 (m, 1H)、3.34 (t,J
= 8.3 Hz, 1H)、3.02 (t,J
= 6.1 Hz, 2H)、2.07 (s, 3H)、1.80 - 1.62 (m, 4H)、1.47 (dt,J
= 22.4, 7.5 Hz, 2H)、1.24 (d,J
= 6.4 Hz, 3H)。利用HRMS (ESI-TOF, MH+
)計算得C43
H75
N3
O31
H+
1130.4457,可得1130.4438。5-胺戊基α-L-吡喃半乳糖-(1→2)-β-D-吡喃半乳糖-(1→3)-2-乙醯胺基-2-去氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-β-D-葡萄糖呱喃醣苷(化合物7
) (5-aminopentyl α-L-galactopyranosyl-(1→2)- β-D-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-β-D-glucopyranoside (Compound7
))
1
H NMR (600 MHz, D2
O) δ 5.40 (d,J
= 3.9 Hz, 1H)、4.92 (d,J
= 3.7 Hz, 1H)、4.65 (d,J
= 7.7 Hz, 1H)、4.61 (d,J
= 7.4 Hz, 1H)、4.53 (d,J
= 7.7 Hz, 1H)、4.50 (d,J
= 8.0 Hz, 1H)、4.41 (t,J
= 6.4 Hz, 1H)、4.34 - 4.24 (m, 2H)、4.15 - 3.56 (m, 34H)、3.33 (t,J
= 8.3 Hz, 1H)、2.97 (t,J
= 7.5 Hz, 2H)、2.09 (s, 3H)、1.74 - 1.66 (m, 4H)、1.49 - 1.42(m, 2H)。13
C NMR (150 MHz、D2
O) δ 174.45、103.70、103.30、102.02、101.95、100.42、98.45、78.77、78.40、77.16、76.09、75.47、75.15、74.79、74.58、74.52、74.50、73.71、72.93、72.09、70.85、70.24、70.14(2C)、69.44、69.20、69.17、69.06、68.43、68.28、67.75、61.76、60.96、60.89、60.33、60.03、51.49、39.47、28.20、27.12、22.30、22.12。利用HRMS (ESI-TOF, MH+
)計算得C43
H76
N2
O31
H+
1117.4505,可得1117.4488。5-胺戊基6-疊氮基-6-去氧-α-L-吡喃半乳糖-(1→2)-β-D-吡喃半乳糖-(1→3)-2-乙醯胺基-2-去氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-β-D-葡萄糖呱喃醣苷(化合物8
) (5-aminopentyl 6-azido-6-deoxy-α-L- galactopyranosyl-(1→2)-β-D-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-β-D-glucopyranoside (Compound8
))
1
H NMR (600 MHz, D2
O) δ 5.46 (d,J
= 3.8 Hz, 1H)、4.92 (d,J
= 3.5 Hz, 1H)、4.65 (d,J
= 7.5 Hz, 1H)、4.60 (d,J
= 8.3 Hz, 1H)、4.53 (d,J
= 7.7 Hz, 1H)、4.53 (d,J
= 8.0 Hz, 1H)、4.41 (t,J
= 6.4 Hz, 1H)、4.34 - 4.24 (m, 2H)、4.18 (s, 1H)、4.09 - 3.59 (m, 32H)、3.33 (t,J
= 8.1 Hz, 2H)、2.99 (t,J
= 7.4 Hz, 2H)、2.08 (s, 3H)、1.78 - 1.64 (m, 4H)、1.55 - 1.44 (m, 2H)。13
C NMR (150 MHz、D2
O) δ 174.36、103.87、103.30、102.29、101.95、100.42、98.41、78.79、78.35、77.17、76.95、75.48、75.11、74.79、74.67、74.53、74.43、73.85、72.93、72.09、70.85、70.15、70.12、69.67、69.61、69.14、69.08、69.05、68.56、68.02、67.78、60.95、60.91、60.33、60.04、51.40、51.25、39.44、28.19、26.96、22.32、22.10。以HRMS (ESI-TOF, MH+
)計算得C43
H75
N5
O30
H+
1142.4570,可得1142.4569。5-胺戊基 6-去氧-6-氟-α-L-吡喃半乳糖-(1→2)-β-D-吡喃半乳糖-(1→3)-2-乙醯胺基-2-去氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-β-D-葡萄糖呱喃醣苷(化合物9
) (5-aminopentyl 6-deoxy-6-fluoro-α-L- galactopyranosyl-(1→2)-β-D-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-β-D-glucopyranoside (Compound9
))
1
H NMR (600 MHz, D2
O) δ 5.40 (d,J
= 3.9 Hz, 1H)、4.91 (d,J
= 3.9 Hz, 1H)、4.69 (m, 1H)、4.64 - 4.60 (m, 2H)、4.57 (d,J
= 8.2 Hz, 1H)、4.52 (d,J
= 7.8 Hz, 1H)、4.49 (d,J
= 8.0 Hz, 1H)、4.39 (m, 2H)、4.26 (d,J
= 2.4 Hz, 1H)、4.12 (d,J
= 2.7 Hz, 1H)、4.09 - 3.56 (m, 31H)、3.32 (t,J
= 8.5 Hz, 1H)、2.99 (t,J
= 7.4 Hz, 2H)、2.07 (s, 3H)、1.71 - 1.66 (m, 4H)、1.49 - 1.44 (m, 2H)。13
C NMR (150 MHz、D2
O) δ 174.38、103.84、103.30、102.05、101.95、100.43、98.98、83.96、82.86、78.79、78.27、77.16、76.69、75.65、75.48、75.09、74.79、74.52、74.47、73.65、72.93、72.09、70.85、70.14、70.12、69.11、68.96、68.36、68.05、67.80、60.95、60.90、60.34、60.03、51.45、39.43、28.18、26.89、22.28、22.10。以HRMS (ESI-TOF, MH+
)計算得C43
H75
FN2
O30
H+
1119.4461,可得1119.4459。5-胺戊基 6-乙炔基-6-去氧-α-L-吡喃半乳糖-(1→2)-β-D-吡喃半乳糖-(1→3)-2-乙醯胺基-2-去氧-β-D-吡喃半乳糖-(1→3)-α-D-吡喃半乳糖-(1→4)-β-D-吡喃半乳糖-(1→4)-β-D-葡萄糖呱喃醣苷(化合物10
) (5-aminopentyl 6-acetylenyl-6-deoxy-α-L- galactopyranosyl-(1→2)-β-D-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-β-D-galactopyranosyl-(1→3)-α-D-Galactopyranosyl-(1→4)-β-D-galactopyranosyl-(1→4)-β-D-glucopyranoside (Compound10
))
1
H NMR (600 MHz, D2
O) δ 5.32 (d,J
= 4.0 Hz, 1H)、4.91 (d,J
= 3.0 Hz, 2H)、4.64 (d,J
= 7.7 Hz, 1H)、4.59 (d,J
= 8.4 Hz, 1H)、4.53 (d,J
= 7.7 Hz, 1H)、4.50 (d,J
= 8.0 Hz, 1H)、4.40 (t,J
= 6.5 Hz, 1H)、4.26 (d,J
= 2.8 Hz, 1H)、4.17 - 4.13 (m, 2H)、4.05 - 3.58 (m, 32H)、3.32 (t,J
= 8.5 Hz, 1H)、3.02 (m, 2H)、2.07 (s, 3H)、1.77 - 1.64 (m, 4H)、1.53 - 1.43 (m, 2H)。13
C NMR (150 MHz、D2
O) δ 177.06、106.53、106.04、104.69、104.60、103.17、102.13、81.52、80.89、79.91、79.26、78.87、78.79、78.22、77.88、77.54、77.27、77.19、76.13、75.67、74.83、74.77、73.69、73.59、72.89、72.81、71.86、71.83、71.28、71.19、70.59、70.21、65.69、65.19、63.68、63.64、63.08、62.77、54.26、42.06、30.89、29.13、25.00、24.81。以HRMS (ESI-TOF, MH+
)計算得C44
H74
N2
O30
H+
1111.4399,可得1111.4397。
實施例
5
:
GH
衍生物之
DT-
共軛物的免疫分析
為了解GH衍生物之DT-共軛物(1-DT至10-DT)的免疫性,以肌肉注射方式將含2微克GH衍生物之GH衍生物之DT-共軛物及2微克之醣脂佐劑C34投予至5隻BALB/c母鼠體內,雙週間隔共投予三次。先前研究指出,在僅投予GH蛋白共軛物而不投予佐劑的情況下,僅能得到低效價的抗GH抗體。在第三次投予後10天,取得各抗原的抗血清,再利用包含94種化學合成聚醣(包含GH1
、GH衍生物2-10
、GH衍生物片段11-30
及其他腫瘤相關醣類抗原)的聚醣微陣列進行分析測試。由於聚醣具有某些化學修飾,該聚醣微陣列亦包含該些功能性連結子,以測試交互反應。
由GH衍生物DT-共軛物(1-DT到10-DT)所引發產生的抗體可專一辨識GH、GH衍生物及GH片段,卻不會結合至其他TACAs及功能性連結子。選取GH、Gb5及SSEA4作為DT-共軛物之標準抗原(第1A圖:GH,第1B圖:Gb5,第1C圖:SSEA4)。由複合醣體所引發之高IgG抗體效價分離的血清可知,其係為一種與T細胞相關之免疫反應。有趣的是,不論是GH-乳糖或是海藻糖衍生物皆不會引發顯著的IgM產生。在IgG對抗GH方面,相較於天然形式之GH-DT共軛物(1-DT),GH-N3
-DT (3-DT)及N3
-GH-DT (8-DT)會引發更高的抗體效價,由GH-F-DT (2-DT)及GH-苯基-DT (4-DT)引發的抗體效價則與天然形式之GH-DT共軛物(1-DT)相當。由GH-N3
-DT (3-DT)及N3
-GH-DT (8-DT)所產生的高效價可推知,疊氮基可作為一種免疫調節劑。用以增加免疫性之機致目前尚不明確,然相較於天然的GH,位於GH-N3 3
或N3
-GH8
之聚醣的N3
特性可能扮演著重要的角色。由GH氟基團所產生的免疫性調節具有位向選擇性(regioselective)。位於GH還原端之葡萄糖之C-6位置的氟基團可引發與天然GH相當的價效,而由GH非還原端海藻糖之C-6位置的氟基團所引發的效價則與GH具有低反應性。有趣的是,由GH-苯基-DT (4-DT)所引發的免疫反應可與GH產生交互反應。該交互反應與先前報導所述之在利用N-苯乙醯基(N-phenylacetyl) GM3或STn作為疫苗時,天然GM3與STn並不會產生交互反應的結果並不相符。抗原GH-苯基NO2
-DT (5-DT)、GH-NO2
-DT (6-DT)、OH-GH-DT (7-DT)、F-GH-DT (9-DT)及乙炔基-GH-DT (10-DT)僅能產生微弱的免疫反應以對抗GH。此外,GH-苯基NO2
-DT (5-DT)及GH-NO2
-DT (6-DT)雖可對苯基NO2
及NO2
醣類相似物產生強烈的免疫反應,卻不會對天然形式之GH相似物產生免疫反應。該結果亦與先前報導所述之TNF-α單一對苯基NO2
突變可引發大量辨識野生型TNF-α之抗體產生的結果不符。有趣的是,由該些複合醣體所引發的抗體對Gb5及SSEA4亦具有相同的辨識功效(第1B-C圖)。因此,該些結果指出,以氟、疊氮基或苯基來修飾Globo H 還原端之C-6位置可引發大量IgG抗體免疫,據以專一地辨識Globo H、Gb5及SSEA。然而,唯有利用疊氮基修飾Globo H非還原端海藻糖之C-6位置可產生強烈的IgG免疫反應。可參照Lee et al.,J. Am. Chem. Soc.
2014, 136, 16844-16853。
進一步利用聚醣微陣列來分析該些疫苗所產生之抗血清中IgG次類別的抗體類型;結果指出,抗體具有顯著量的IgG1、IgG2b、IgG2c及IgG3,以及少量的IgG2a。此外,在具有高量IgG3抗體的抗血清中,IgG1次類別具有最高的含量,其係為一種典型的抗醣類反應且與T細胞所產生的免疫反應相關。
利用流式細胞儀來檢測由GH-DT (1-DT)、GH-F-DT (2-DT)、GH-N3
-DT (3-DT)、GH-苯基-DT (4-DT)及N3
-GH-DT (8-DT)所產生之小鼠抗血清於辨識GH表現MCF7人類乳癌細胞株的能力(第2圖)。可預期地,相較於未經處理的小鼠,由GH-DT (1-DT)所引發的抗血清可與GH表現MCF7細胞產生顯著的反應。由GH衍生物-DT (2-DT、3-DT、4-DT及8-DT)所引發的抗血清亦可辨識MCF7細胞。
實施例
6
:
GH
衍生物
DT
共軛物之與補體相關之細胞毒殺
利用具有GH表現之MCF7癌細胞株來分析與補體相關之細胞毒殺(Complement-dependent cytoxicity, CDC)(第3圖)。將MCF-7細胞種植於96孔洞細胞培養盤中,每孔洞的細胞數量為104
細胞。於37°C放置至隔日後,將細胞培養液置換為100微升的抗血清/補體混合液,再於37°C的環境中培養2小時。為製備抗血清/補體混合液,以包含20%兔子補體(Life Technologies)之細胞培養液20倍稀釋抗血清。培養後,利用CytoTox 96®
非放射活化細胞毒殺試劑套組(CytoTox 96®
Non-Radioactive Cytotoxicity Assay kit, Promega, Fitchburg, WI)並依據其使用說明來分析由抗血清所引發的細胞毒殺反應。利用未經處理之Blab/c小鼠的血清標準化由抗血清引發的細胞毒殺,並以相對倍數來表示結果。
相較於未經處理之小鼠的血清,由GH-DT (1-DT)、GH-F-DT (2-DT)、GH-N3
-DT (3-DT)、GH-苯基-DT (4-DT)及N3
-GH-DT (8-DT)刺激免疫反應所得之抗血清可顯著地誘發癌細胞產生細胞毒殺反應。由GH-苯基-DT (4-DT)及N3
-GH-DT (8-DT)所得之抗血清所引發的細胞毒殺反應與天然形式之GH-DT (1-DT)相當。有趣的是,相較於GH-DT (1-DT),由GH-F-DT (2-DT)或GH-N3
-DT (3-DT)疫苗所得之抗血清可誘發更高量(15%)的癌細胞毒殺反應;該結果顯示,該些衍生物可作為更具治療功效的疫苗。
本發明建立了一套用以化學酵素合成GH衍生物及其免疫共軛物的策略。利用聚醣微陣列來評估相較於天然形式的GH-DT (1-DT),GH衍生物共軛物的免疫特性。結果指出,以氟、疊氮基或苯基來修飾Globo H 的還原端可引發大量IgG抗體免疫,據以專一地辨識Globo H、Gb5及SSEA,而唯有Globo H之疊氮基-海藻糖衍生物可產生強烈的IgG免疫反應。此外,由GH-DT (1-DT)、GH-F-DT (2-DT)、GH-N3
-DT (3-DT)、GH-苯基-DT (4-DT)及N3
-GH-DT (8-DT)所產生的抗體可辨識具有GH表現的腫瘤細胞(MCF-7),且可引發可對抗腫瘤細胞之與補體相關的細胞毒殺反應。相較於GH-DT (1-DT),GH-F-DT (2-DT)及GH-N3
-DT (3-DT)疫苗具有更高的癌細胞毒殺功效,可作為新一代修飾醣抗原結構之疫苗。
方法、材料及儀器
所有的化學藥品及試劑皆是購買自Acros, Echo chemical, Merck Sigma-Aldrich, Fluka,且無需進一步純化即可直接使用。所有對空氣或溼度敏感的試劑或中間物皆係於含氬環境中操作使用。在高真空中加熱乾燥分子篩4Å (Acros)。以位於矽膠60 F254
盤(2毫米,Merck)之薄層色層分析偵測反應的進行,並利用紫外光照射及以酸鈰鉬酸銨(acid ceric ammonium molybdate)或對茴香醛(p
-anisaldehyde)染色後進行觀測。於矽膠(40-63微米,Merck)或LiChroprep RP-18 (40-63微米,Merck)進行快速管柱色層分析。透析膜(纖維素酯,MCCO = 10,000)在使用前先以二次水洗滌。NMR光譜是以Brüker Advance 600記錄位於600 MHz (1
H NMR)及150 MHz (13
C HMR)的光譜。以ppm (δ 標)來標記化學位移(chemical shift),其係以相對於氘代氯仿(deuterated chloroform,δ= 4.80 ppm)、氘代水(δ= 4.80 ppm)或氘代甲醇(δ= 3.31 ppm)之殘基質子及碳訊號進行校正。以1
H NMR或光譜的化學位移來計算Hz的耦合常數(Coupling constant)。以下列方式來表述結果:化學位移、多重性(multiplicity,s =單、d=雙、t =三、q =四、 m=多、br =廣)、Hz 的整合及耦合常數(intergration and coupling constant,J
)。以APEX-ultra 9.4 T FTICR-MS (Bruker Daltonics)記錄高解析ESI質譜。利用Bruker Ultraflex II TOF/TOF200光譜儀,並以芥子酸(sinapinic acid)作為基質,來計錄MALDI-TOF 光譜。與Alexa Fluor 647結合之山羊抗-小鼠IgG抗體、與DyLight 649結合之山羊抗-小鼠IgM抗體、與Alexa Fluor 488結合之山羊抗-小鼠IgG1抗體、與Alexa Flour 594結合之山羊抗-小鼠IgG2a抗體、與Cy3結合之山羊抗-小鼠IgG2b抗體、與R-PE結合之抗-小鼠IgG2c抗體及與Alexa Fluor 647結合之山羊抗-小鼠IgG3抗體皆係購買自Jackson Immunoresearch。利用微陣列螢光片讀取器(GenePix 4300A; Molecular Devices Corporation)以635奈米、594 奈米、532奈米或488奈米的波長來掃瞄微陣列玻片。以GenePix Pro-6.0軟體(Axon Instruments, Union City, CA, USA)分析螢光資料。白喉類毒素CRM 197是購買自PF
enex 公司。
所有的核苷酸、醣類、糖核苷酸及化學物質皆購買自Sigma-Aldrich (St. Louis, MO)。依據已知步驟來進行轉殖、過量表現、純化及檢測酵素活性。
用以合成
GH-
衍生單酯的方法
將GH衍生物(2-3毫克,1等量)溶於無水二甲基甲醯胺(anhydrous dimethylformamide, DMF)溶液中。再加入對硝基苯基酯類連結子(5-6毫克,5等量),並於室溫攪拌1-5小時。利用薄層色層分析,並以3:2:2之比例的正丁醇/乙酸/水作為顯影溶劑來偵測反應進行。取得最佳產量後,以真空且不加熱的方式濃縮反應混合物以移除DMF。以逆相(C18)管柱層析法來純化,且逐漸以包含1%醋酸之水及甲醇:水 = 7:3之沖提液來沖提產物。冷凍乾燥溶液,直到產生淡黃色之固態GH-衍生物單酯(1.5-2毫克,60~80%)。
GH-
衍生物複合醣體的製備方法
將DT溶於100 mM之生理食鹽水緩衝液(pH 7.9,每毫升5毫克)中,再加入30-40等量之GH-衍生物單酯。於室溫緩慢攪拌混合液24小時。以水稀釋混合液,再利用Amicon Ultra-0.5(10 kDa)以10次去離子水離心產物。冷凍乾燥溶液,直到得到白色粉末。以MALDI-TOF (正模式,基質芥子酸,水)來分析所得GH-衍生物DT共軛物中寡醣的嵌合數量。
微陣列製備及偵測
為製備微陣列,將化合物1-30
、9種功能性連結子及55種具有胺戊基的寡醣溶於10mM之列印緩衝液 (300 mM磷酸緩衝液,0.005%妥文20,pH 8.5)。以機器探頭(SMP3; TeleChem International)自96孔洞盤取得約0.6奈升之溶液後,將聚醣列印(BioDot; Cartesian Technologies)至具有NHS塗佈之玻璃片(Nexterion H slide; SCHOTT North America)上。微陣列玻片共具16個網格,其中各網格皆是由20列× 10欄所組成。列印出的玻片在80%溼度的環境中反應1小時後,再乾燥至隔日。將該些玻片保存於室溫的乾燥箱中,以供後續使用。
細胞株及流式細胞儀分析
將人類乳癌細胞株MCF-7培養於包含10%胎牛血清、1倍抗生素-抗真菌(Antimycotic, Life Technologies)及胰島素(每毫升50毫克)的DMEM細胞培養液(Life Technologies, Carlsbad, CA)中。為進行流式細胞儀分析,收集細胞後,以500 g的轉速離心3分鐘,再將細胞懸浮於FACS染色/洗滌緩衝液(1%胎牛血清、溶於生理食鹽水之0.1% NaN3
)。將細胞(2.5 x 105
)培養於經GH衍生物處理之Balb/c小鼠的抗血清(1/10稀釋於50微升之FACS染色/洗滌緩衝液)中,於4°C反應2小時。將未經處理之Balb/c小鼠的血清作為實驗對照組。以1毫升之FACS染色/洗滌緩衝液洗滌2次後,將細胞培養於以FITC標記之抗-小鼠IgG/IgM抗體(1/20稀釋,BD Biosciences, San Jose, CA),於4°C作用30分鐘。再次以1毫升之FACS染色/洗滌緩衝液洗滌2次後,利用流式細胞儀進行分析。利用FACSCanto (Becton Dickinson, Franklin Lakes, NJ)、FACSDiva軟體(Becton Dickinson)及FlowJo (Tree Star, Ashland, OR)來分析各檢體。
小鼠劑量及免疫方法
為比較GH衍生物疫苗(1-DT到10-DT),以肌肉注射方式將醣脂C34注入10組小鼠體內(每組5隻,8週大之Balb/c母鼠,購買自台灣BioLASCO)。每2週投予一次疫苗,共3次。各疫苗包含2微克之GH衍生物及2微克之C34。將投予生理食鹽水之小鼠作為對照組。在首次注射前及第3次注射後10天,採取小鼠血液。以4,000×g的轉速離心10分鐘,以取得血清。以聚醣微陣列分析各血清反應。
以聚醣微陣列分析血清
以1% BSA/PBST緩衝液(PBST緩衝液:生理食鹽水及0.05%妥文-20,pH 7.4)稀釋小鼠血清。將Superblock阻斷緩衝液(Pierce)加入聚醣微陣列,並於4°C反應1小時;之後,以PBST緩衝液洗滌3次。將稀釋後的血清加入聚醣微陣列中,並於4°C反應1小時。洗滌移除過量的血清抗體,再分別加入與Alexa Fluor 647結合之山羊抗-小鼠IgG抗體或與DyLight 649結合之山羊抗-小鼠IgM抗體(作為第二抗體),於避光的環境中,置於4°C 作用1小時。以PBST洗滌3次後,利用微陣列螢光片讀取器(GenePix 4300A; Molecular Devices Corporation)以635奈米之波長進行掃瞄,再以GenePix Pro-6.0分析軟體(Axon Instruments, Union City, CA, USA)分析掃瞄影像。
抗體次類別分析
如上述方式分析抗體的次類別。分別將與Alexa Flour 594結合之山羊抗-小鼠IgG2a抗體、與Cy3結合之山羊抗-小鼠IgG2b抗體、與R-PE結合之抗-小鼠IgG2c抗體及與Alexa Fluor 647結合之山羊抗-小鼠IgG3抗體以400倍稀釋比例加入微陣列中,再進行反應及洗滌。
其他實施方式
可以任何組合方式組合本說明書所揭示之技術特徵。亦可以能產生相同、等量或相似功效之替代性技術來取代本說明書所揭示之各技術特徵。因此,除非另有定義,否則本揭示內容中各技術特徵僅作為能產生等量或相似特徵之範例。
雖然上文實施方式中揭露了本發明的具體實施例,然其並非用以限定本發明,本發明所屬技術領域中具有通常知識者,在不悖離本發明之原理與精神的情形下,當可對其進行各種更動與修飾,因此本發明之保護範圍當以附隨申請專利範圍所界定者為準。
參考文獻 (1) Hakomori, S. Adv Cancer Res 1989, 52, 257. (2) Hakomori, S. Curr. Opin. Immunol. 1991, 3, 646. (3) (a) Astronomo, R. D.; Burton, D. R. Nat. Rev. Drug Discovery 2010, 9, 308. (b) Buskas, T.; Thompson, P.; Boons, G. J. Chem. Commun. 2009, 5335. (c) Wilson, R. M.; Danishefsky, S. J. J. Am. Chem. Soc. 2013, 135, 14462. (4) Berti, F.; Adamo, R. ACS Chem. Biol. 2013, 8, 1653. (5) (a) Bundle, D. R.; Rich, J. R.; Jacques, S.; Yu, H. N.; Nitz, M.; Ling, C. C. Angew. Chem. Int. Ed. 2005, 44, 7725. (b) Wu, X.; Lipinski, T.; Paszkiewicz, E.; Bundle, D. R. Chemistry 2008, 14, 6474. (6) (a) Lo-Man, R.; Vichier-Guerre, S.; Perraut, R.; Deriaud, E.; Huteau, V.; BenMohamed, L.; Diop, O. M.; Livingston, P. O.; Bay, S.; Leclerc, C. Cancer Res. 2004, 64, 4987. (b) Kagan, E.; Ragupathi, G.; Yi, S. S.; Reis, C. A.; Gildersleeve, J.; Kahne, D.; Clausen, H.; Danishefsky, S. J.; Livingston, P. O. Cancer Immunol. Immunother. 2005, 54, 424. (7) Ragupathi, G.; Koide, F.; Livingston, P. O.; Cho, Y. S.; Endo, A.; Wan, Q.; Spassova, M. K.; Keding, S. J.; Allen, J.; Ouerfelli, O.; Wilson, R. M.; Danishefsky, S. J. J. Am. Chem. Soc. 2006, 128, 2715. (8) (a) Ingale, S.; Wolfert, M. A.; Gaekwad, J.; Buskas, T.; Boons, G. J. Nat. Chem. Biol. 2007, 3, 663. (b) Buskas, T.; Ingale, S.; Boons, G. J. Angew. Chem. Int. Ed. 2005, 44, 5985. (9) (a) Liu, C. C.; Ye, X. S. Glycoconj J 2012, 29, 259. (b) Yin, Z.; Huang, X. J. Carbohydr. Chem. 2012, 31, 143. (10) (a) Miles, D.; Roche, H.; Martin, M.; Perren, T. J.; Cameron, D. A.; Glaspy, J.; Dodwell, D.; Parker, J.; Mayordomo, J.; Tres, A.; Murray, J. L.; Ibrahim, N. K.; Theratope Study, G. Oncologist 2011, 16, 1092. (b) Holmberg, L. A.; Sandmaier, B. M. Expert Rev. Vaccines. 2004, 3, 655. (c) Kirkwood, J. M.; Ibrahim, J.; Lawson, D. H.; Atkins, M. B.; Agarwala, S. S.; Collins, K.; Mascari, R.; Morrissey, D. M.; Chapman, P. B. J Clin Oncol 2001, 19, 1430. (d) Eggermont, A. M. Nat Rev Clin Oncol 2009, 6, 256. (11) Bundle, D. R. Nat. Chem. Biol. 2007, 3, 605. (12) (a) Kannagi, R.; Levery, S. B.; Ishigami, F.; Hakomori, S.; Shevinsky, L. H.; Knowles, B. B.; Solter, D. J. Biol. Chem. 1983, 258, 8934. (b) Menard, S.; Tagliabue, E.; Canevari, S.; Fossati, G.; Colnaghi, M. I. Cancer Res. 1983, 43, 1295. (c) Bremer, E. G.; Levery, S. B.; Sonnino, S.; Ghidoni, R.; Canevari, S.; Kannagi, R.; Hakomori, S. J. Biol. Chem. 1984, 259, 14773. (13) (a) Canevari, S.; Fossati, G.; Balsari, A.; Sonnino, S.; Colnaghi, M. I. Cancer Res. 1983, 43, 1301. (b) Huang, Y. L.; Hung, J. T.; Cheung, S. K.; Lee, H. Y.; Chu, K. C.; Li, S. T.; Lin, Y. C.; Ren, C. T.; Cheng, T. J.; Hsu, T. L.; Yu, A. L.; Wu, C. Y.; Wong, C. H. Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 2517. (c) Lou, Y. W.; Wang, P. Y.; Yeh, S. C.; Chuang, P. K.; Li, S. T.; Wu, C. Y.; Khoo, K. H.; Hsiao, M.; Hsu, T. L.; Wong, C. H. Proc. Natl. Acad. Sci. U. S. A. 2014, 111, 2482. (14) Gilewski, T.; Ragupathi, G.; Bhuta, S.; Williams, L. J.; Musselli, C.; Zhang, X. F.; Bornmann, W. G.; Spassova, M.; Bencsath, K. P.; Panageas, K. S.; Chin, J.; Hudis, C. A.; Norton, L.; Houghton, A. N.; Livingston, P. O.; Danishefsky, S. J. Proc. Natl. Acad. Sci. U. S. A. 2001, 98, 3270. (15) (a) Tsai, T. I.; Lee, H. Y.; Chang, S. H.; Wang, C. H.; Tu, Y. C.; Lin, Y. C.; Hwang, D. R.; Wu, C. Y.; Wong, C. H. J. Am. Chem. Soc. 2013, 135, 14831. (b) Burkhart, F.; Zhang, Z.; Wacowich-Sgarbi, S.; Wong, C. H. Angew. Chem. Int. Ed. 2001, 40, 1274. (16) (a) Slovin, S. F.; Ragupathi, G.; Adluri, S.; Ungers, G.; Terry, K.; Kim, S.; Spassova, M.; Bornmann, W. G.; Fazzari, M.; Dantis, L.; Olkiewicz, K.; Lloyd, K. O.; Livingston, P. O.; Danishefsky, S. J.; Scher, H. I. Proc. Natl. Acad. Sci. U. S. A. 1999, 96, 5710. (b) Wang, Z. G.; Williams, L. J.; Zhang, X. F.; Zatorski, A.; Kudryashov, V.; Ragupathi, G.; Spassova, M.; Bornmann, W.; Slovin, S. F.; Scher, H. I.; Livingston, P. O.; Lloyd, K. O.; Danishefsky, S. J. Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 2719. (17) (a) Yin, Z. J.; Huang, X. F. J. Carbohydr. Chem. 2012, 31, 143. (b) Liu, C. C.; Ye, X. S. Glycoconjugate J. 2012, 29, 259. (18) (a) Jennings, H. J.; Roy, R.; Gamian, A. J. Immunol. 1986, 137, 1708. (b) Krug, L. M.; Ragupathi, G.; Ng, K. K.; Hood, C.; Jennings, H. J.; Guo, Z.; Kris, M. G.; Miller, V.; Pizzo, B.; Tyson, L.; Baez, V.; Livingston, P. O. Clin Cancer Res 2004, 10, 916. (c) Krug, L. M.; Ragupathi, G.; Hood, C.; George, C.; Hong, F.; Shen, R.; Abrey, L.; Jennings, H. J.; Kris, M. G.; Livingston, P. O. Cancer Immunol. Immunother. 2012, 61, 9. (19) (a) Wu, J.; Guo, Z. Bioconjugate Chem. 2006, 17, 1537. (b) Wang, Q.; Ekanayaka, S. A.; Wu, J.; Zhang, J.; Guo, Z. Bioconjugate Chem. 2008, 19, 2060. (c) Yang, F.; Zheng, X. J.; Huo, C. X.; Wang, Y.; Zhang, Y.; Ye, X. S. ACS Chem. Biol. 2011, 6, 252. (d) Sahabuddin, S.; Chang, T. C.; Lin, C. C.; Jan, F. D.; Hsiao, H. Y.; Huang, K. T.; Chen, J. H.; Horng, J. C.; Ho, J. A. A.; Lin, C. C. Tetrahedron 2010, 66, 7510. (20) Pan, Y.; Chefalo, P.; Nagy, N.; Harding, C.; Guo, Z. J. Med. Chem. 2005, 48, 875. (21) (a) Grunewald, J.; Tsao, M. L.; Perera, R.; Dong, L.; Niessen, F.; Wen, B. G.; Kubitz, D. M.; Smider, V. V.; Ruf, W.; Nasoff, M.; Lerner, R. A.; Schultz, P. G. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 11276. (b) Grunewald, J.; Hunt, G. S.; Dong, L.; Niessen, F.; Wen, B. G.; Tsao, M. L.; Perera, R.; Kang, M.; Laffitte, B. A.; Azarian, S.; Ruf, W.; Nasoff, M.; Lerner, R. A.; Schultz, P. G.; Smider, V. V. Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 4337. (22) (a) Hoffmann-Roder, A.; Johannes, M. Chem. Commun. 2011, 47, 9903. (b) Hoffmann-Roder, A.; Kaiser, A.; Wagner, S.; Gaidzik, N.; Kowalczyk, D.; Westerlind, U.; Gerlitzki, B.; Schmitt, E.; Kunz, H. Angew. Chem. Int. Ed. 2010, 49, 8498. (c) Oberbillig, T.; Mersch, C.; Wagner, S.; Hoffmann-Roder, A. Chem. Commun. 2012, 48, 1487. (23) (a) Park, T. K.; Kim, I. J.; Hu, S. H.; Bilodeau, M. T.; Randolph, J. T.; Kwon, O.; Danishefsky, S. J. J. Am. Chem. Soc. 1996, 118, 11488. (b) Bilodeau, M. T.; Park, T. K.; Hu, S. H.; Randolph, J. T.; Danishefsky, S. J.; Livingston, P. O.; Zhang, S. L. J. Am. Chem. Soc. 1995, 117, 7840. (24) Lassaletta, J. M.; Schmidt, R. R. Liebigs Ann. 1996, 1417. (25) Zhu, T.; Boons, G. J. Angew. Chem. Int. Ed. 1999, 38, 3495. (26) Bosse, F.; Marcaurelle, L. A.; Seeberger, P. H. J. Org. Chem. 2002, 67, 6659. (27) Werz, D. B.; Castagner, B.; Seeberger, P. H. J. Am. Chem. Soc. 2007, 129, 2770. (28) Wang, Z.; Zhou, L.; El-Boubbou, K.; Ye, X. S.; Huang, X. J. Org. Chem. 2007, 72, 6409. (29) Huang, C. Y.; Thayer, D. A.; Chang, A. Y.; Best, M. D.; Hoffmann, J.; Head, S.; Wong, C. H. Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 15. (30) Su, D. M.; Eguchi, H.; Yi, W.; Li, L.; Wang, P. G.; Xia, C. Org. Lett. 2008, 10, 1009. (31) Zhang, J.; Kowal, P.; Fang, J.; Andreana, P.; Wang, P. G. Carbohydr. Res. 2002, 337, 969. (32) Shao, J.; Zhang, J.; Kowal, P.; Lu, Y.; Wang, P. G. Biochem. Biophys. Res. Commun. 2002, 295, 1. (33) Cai, X. Q.; Tsuchikama, K.; Janda, K. D. J. Am. Chem. Soc. 2013, 135, 2971.
無
第1A-C圖是關於IgG抗體之圖式,該些IgG抗體是由GH衍生物-DT共軛物所製備,且可分別用以對抗GH、Gb5及SSEA4。
第2圖是關於由GH衍生物-DT共軛物所製備之可辨識GH表現腫瘤細胞(MCF-7)的小鼠抗體。
第3圖是關於由GH衍生物所產生的抗體,其係可引發與補體相關之細胞毒殺 (complement-dependent cytotoxicity, CDC)以消除GH表現腫瘤細胞。
Claims (19)
- 一種免疫組合物,包含:一聚醣共軛物(glycan conjugate),其係包含至少一種與一連結子(linker)結合之聚醣及一載體(carrier),其中該至少一種聚醣是藉由該連結子而與該載體形成共軛;其中該至少一種與該連結子結合之聚醣具有式(II)之化學結構:
- 如請求項1所述之免疫組合物,其中該載體是一蛋白、一脂質、一脂質化蛋白、一病毒、一胜肽或一醣肽之樹枝狀聚合物(dendrimer)。
- 如請求項2所述之免疫組合物,其中該載體蛋白是選自由破傷風類毒素(tetanus toxoid,TT)、 白喉類毒素(diphtheria toxoid,DT)、白喉類毒素交互反應物質197(diphtheria toxin cross-reacting material 197,CRM197)、破傷風類毒素之片段C(fragment C of TT)、鍵孔血藍蛋白(Keyhole limpet hemocyanin,KLH)、胎牛血清白蛋白(bovine serum albumin,BSA)、蛋白D(protein D)、外膜蛋白(outer-membrane protein,OMP)及肺炎球菌溶血素(pneumolysin)所組成的群組。
- 如請求項3所述之免疫組合物,其中該載體蛋白是CRM197,且該聚醣共軛物具有式(III)之化學結構:
- 如請求項1-4任一項所述之免疫組合物,其中該連結子是一異-(hetero-)或同-(homo-)雙功能連結子。
- 如請求項5所述之免疫組合物,其中該連結子是一胺基活化(amino-active)之同-雙功能連結子,具有2-20個的碳原子,可分別與該至少一種聚醣及該載體蛋白形成醯胺鍵(amide bond)。
- 如請求項1-4任一項所述之免疫組合物,更包含一佐劑。
- 如請求項7所述之免疫組合物,其中該佐劑是C34、Gluco-C34、7DW8-5、C17、C23、C30、α-神經醯胺半乳糖(α-galactoceramide)、鋁鹽、鯊烯(Squalene)、MF59或QS-21。
- 一種癌症疫苗,包含如請求項1-4任一項所述之免疫組合物及一藥學上可接受之賦形劑。
- 一種如請求項1-4任一項所述之免疫組合物的用途,其係用於製備一藥物以治療一癌症病患,其中該免疫組合物可誘發癌細胞產生細胞毒殺反應、引發對抗癌症的免疫反應、產生可專一結合至及/或中和一或多種癌細胞表面抗原的抗體,其中該一或多種癌細胞表面抗原係選自由Globo H、SSEA-3及SSEA-4所組成的群組。
- 如請求項10所述之用途,其中該抗體主要是IgG抗體。
- 如請求項10所述之用途,其中該癌症是選自由腦癌、肺癌、乳癌、口腔癌、食道癌、胃癌、肝癌、膽管癌、胰臟癌、大腸直腸癌、腎臟癌、骨癌、皮膚癌、子宮頸癌、卵巢癌及前列腺癌所組成的群組。
- 如請求項10所述之用途,其中該癌症會表現Globo H、SSEA3及/或SSEA4抗原。
- 一種用以製備如請求項1所述之免疫組合物的方法,包含令一載體、至少一種聚醣及一連接子進行共軛反應(conjugation reaction),以製備如請求項1所述之免疫組合物。
- 如請求項14所述之方法,其中該連結子包含至少一硫原子、羧酸酯基(carboxylate group)、醯胺基(amide group)、氨基甲酸酯基(carbamate group)、碳酸基(carbonate group)、硫代氨基甲酸酯基(thiocarbamate group)、硫碳酸基(thiocarbonate group)、硫醚基(thioether group)、丁二醯胺基(succinamide group)、正-羥基丁二醯胺基(n-hydroxy succinamide group)或其組合物。
- 一種如式(I)之化合物:
- 一種用以製備如請求項1所述之免疫組合物的方法,包含:(i)提供一種式(X)之化合物:
- 如請求項17所述之方法,其中該胺基活化的雙功能連結子是一具有4到6個碳原子的二羧酸(dicarboxylic acid)。
- 如請求項17所述之方法,其中該載體是一蛋白、一脂質、一脂質化蛋白、一病毒、一胜肽或一醣肽之樹枝狀聚合物。
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201462040756P | 2014-08-22 | 2014-08-22 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW201607557A TW201607557A (zh) | 2016-03-01 |
TWI587871B true TWI587871B (zh) | 2017-06-21 |
Family
ID=55351272
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW104127282A TWI587871B (zh) | 2014-08-22 | 2015-08-21 | 新穎之聚醣共軛物及其用途 |
Country Status (12)
Country | Link |
---|---|
US (1) | US10155823B2 (zh) |
EP (1) | EP3183262B1 (zh) |
JP (1) | JP6401380B2 (zh) |
KR (1) | KR102003138B1 (zh) |
CN (1) | CN106573962B (zh) |
AU (1) | AU2015305332B2 (zh) |
CA (1) | CA2959030C (zh) |
ES (1) | ES2820303T3 (zh) |
MX (1) | MX2017002333A (zh) |
NZ (1) | NZ729243A (zh) |
TW (1) | TWI587871B (zh) |
WO (1) | WO2016029071A1 (zh) |
Families Citing this family (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7960139B2 (en) | 2007-03-23 | 2011-06-14 | Academia Sinica | Alkynyl sugar analogs for the labeling and visualization of glycoconjugates in cells |
EP2318832B1 (en) | 2008-07-15 | 2013-10-09 | Academia Sinica | Glycan arrays on ptfe-like aluminum coated glass slides and related methods |
US11377485B2 (en) | 2009-12-02 | 2022-07-05 | Academia Sinica | Methods for modifying human antibodies by glycan engineering |
US10087236B2 (en) | 2009-12-02 | 2018-10-02 | Academia Sinica | Methods for modifying human antibodies by glycan engineering |
US10338069B2 (en) | 2010-04-12 | 2019-07-02 | Academia Sinica | Glycan arrays for high throughput screening of viruses |
US10130714B2 (en) | 2012-04-14 | 2018-11-20 | Academia Sinica | Enhanced anti-influenza agents conjugated with anti-inflammatory activity |
US9914956B2 (en) | 2012-08-18 | 2018-03-13 | Academia Sinica | Cell-permeable probes for identification and imaging of sialidases |
EP3013365B1 (en) | 2013-06-26 | 2019-06-05 | Academia Sinica | Rm2 antigens and use thereof |
US9782476B2 (en) | 2013-09-06 | 2017-10-10 | Academia Sinica | Human iNKT cell activation using glycolipids with altered glycosyl groups |
US10150818B2 (en) | 2014-01-16 | 2018-12-11 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
JP2017507118A (ja) | 2014-01-16 | 2017-03-16 | アカデミア シニカAcademia Sinica | がんの処置および検出のための組成物および方法 |
TWI687428B (zh) | 2014-03-27 | 2020-03-11 | 中央研究院 | 反應性標記化合物及其用途 |
KR102512592B1 (ko) | 2014-05-27 | 2023-03-21 | 아카데미아 시니카 | 항-her2 글리코항체 및 이의 용도 |
CA2950415A1 (en) | 2014-05-27 | 2015-12-03 | Academia Sinica | Anti-cd20 glycoantibodies and uses thereof |
EP3149045B1 (en) | 2014-05-27 | 2023-01-18 | Academia Sinica | Compositions and methods relating to universal glycoforms for enhanced antibody efficacy |
US10118969B2 (en) | 2014-05-27 | 2018-11-06 | Academia Sinica | Compositions and methods relating to universal glycoforms for enhanced antibody efficacy |
KR102494193B1 (ko) | 2014-05-28 | 2023-01-31 | 아카데미아 시니카 | 항-tnf-알파 글리코항체 및 이의 용도 |
KR102422375B1 (ko) | 2014-09-08 | 2022-07-18 | 아카데미아 시니카 | 당지질을 사용한 인간 iNKT 세포 활성화 |
US9975965B2 (en) | 2015-01-16 | 2018-05-22 | Academia Sinica | Compositions and methods for treatment and detection of cancers |
US10495645B2 (en) | 2015-01-16 | 2019-12-03 | Academia Sinica | Cancer markers and methods of use thereof |
EP3248005B1 (en) * | 2015-01-24 | 2020-12-09 | Academia Sinica | Novel glycan conjugates and methods of use thereof |
JP2019515876A (ja) | 2016-03-08 | 2019-06-13 | アカデミア シニカAcademia Sinica | N−グリカンおよびそのアレイのモジュール合成のための方法 |
CN109963868B (zh) | 2016-08-22 | 2023-11-14 | 醣基生医股份有限公司 | 抗体、结合片段及使用方法 |
WO2018129624A1 (en) * | 2017-01-13 | 2018-07-19 | National Research Council Of Canada | Method of optimizing peptide immuno-epitope by glycosylation, optimized peptide thereof and its use for conjugate vaccines |
CN108329362B (zh) * | 2018-03-20 | 2020-10-09 | 江南大学 | 一种革兰氏阳性菌表面荚膜多糖结构衍生物的制备方法 |
CN115850913B (zh) * | 2022-12-02 | 2024-03-08 | 西南石油大学 | 一种环保型纳米膨胀阻燃剂mBN@LDH@PATP及环氧树脂纳米复合材料的制备方法 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050222398A1 (en) * | 1997-04-16 | 2005-10-06 | Danishefsky Samuel J | Glycopeptide conjugates and uses thereof |
TW201100098A (en) * | 2009-06-16 | 2011-01-01 | Academia Sinica | Globo H and related anti-cancer vaccines with novel glycolipid adjuvants |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP4308918B2 (ja) | 1997-04-16 | 2009-08-05 | スローン−ケッタリング インスティトゥート フォア キャンサー リサーチ | (2,6)−STエピトープクラスターを有するα−O−結合複合糖質、その製造方法および使用 |
WO1999048515A1 (en) * | 1998-03-25 | 1999-09-30 | Sloan-Kettering Institute For Cancer Research | Trimeric antigenic o-linked glycopeptide conjugates, methods of preparation and uses thereof |
US6797275B1 (en) * | 1998-12-04 | 2004-09-28 | The United States Of America As Represented By The Department Of Health And Human Services | Method of immunizing humans against Salmonella typhi using a Vi-rEPA conjugate vaccine |
AU2009268937A1 (en) * | 2008-06-16 | 2010-01-14 | Aj Park | Compositions for inducing immune responses specific to Globo H and SSEA3 and uses thereof in cancer treatment |
CN105535955B (zh) * | 2009-06-16 | 2019-04-23 | 中央研究院 | Globo h及含新颖糖脂质佐剂的相关抗癌疫苗 |
TWI563091B (en) | 2012-08-20 | 2016-12-21 | Academia Sinica | Large scale enzymatic synthesis of oligosaccharides |
-
2015
- 2015-08-21 MX MX2017002333A patent/MX2017002333A/es unknown
- 2015-08-21 JP JP2017510554A patent/JP6401380B2/ja active Active
- 2015-08-21 WO PCT/US2015/046197 patent/WO2016029071A1/en active Application Filing
- 2015-08-21 AU AU2015305332A patent/AU2015305332B2/en active Active
- 2015-08-21 KR KR1020177007433A patent/KR102003138B1/ko active IP Right Grant
- 2015-08-21 EP EP15833684.2A patent/EP3183262B1/en active Active
- 2015-08-21 US US15/505,763 patent/US10155823B2/en active Active
- 2015-08-21 TW TW104127282A patent/TWI587871B/zh active
- 2015-08-21 NZ NZ729243A patent/NZ729243A/en unknown
- 2015-08-21 CA CA2959030A patent/CA2959030C/en active Active
- 2015-08-21 ES ES15833684T patent/ES2820303T3/es active Active
- 2015-08-21 CN CN201580045205.4A patent/CN106573962B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050222398A1 (en) * | 1997-04-16 | 2005-10-06 | Danishefsky Samuel J | Glycopeptide conjugates and uses thereof |
TW201100098A (en) * | 2009-06-16 | 2011-01-01 | Academia Sinica | Globo H and related anti-cancer vaccines with novel glycolipid adjuvants |
TW201328705A (zh) * | 2009-06-16 | 2013-07-16 | Academia Sinica | 免疫原性組合物及其用途 |
Also Published As
Publication number | Publication date |
---|---|
EP3183262B1 (en) | 2020-07-01 |
JP2017525714A (ja) | 2017-09-07 |
EP3183262A1 (en) | 2017-06-28 |
EP3183262A4 (en) | 2018-03-28 |
NZ729243A (en) | 2018-08-31 |
ES2820303T3 (es) | 2021-04-20 |
MX2017002333A (es) | 2017-08-28 |
US20170275389A1 (en) | 2017-09-28 |
US10155823B2 (en) | 2018-12-18 |
CA2959030C (en) | 2018-12-18 |
WO2016029071A1 (en) | 2016-02-25 |
TW201607557A (zh) | 2016-03-01 |
KR102003138B1 (ko) | 2019-07-23 |
CA2959030A1 (en) | 2016-02-25 |
JP6401380B2 (ja) | 2018-10-10 |
CN106573962A (zh) | 2017-04-19 |
AU2015305332A1 (en) | 2017-03-09 |
AU2015305332B2 (en) | 2018-04-12 |
CN106573962B (zh) | 2020-06-05 |
KR20170042770A (ko) | 2017-04-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI587871B (zh) | 新穎之聚醣共軛物及其用途 | |
EP3013365B1 (en) | Rm2 antigens and use thereof | |
AU2021200283B2 (en) | Novel glycan conjugates and methods of use thereof | |
EP3013347B1 (en) | Glycan conjugates and use thereof | |
EP2922575B1 (en) | Trioxacarcins, trioxacarcin-antibody conjugates, and uses thereof | |
KR20180053599A (ko) | 보다 높은 탄수화물 항원 밀도 및 신규한 사포닌 애쥬번트를 갖는 백신 | |
US10973910B1 (en) | Neoglycoconjugates as vaccines and therapeutic tools | |
BR112020018974A2 (pt) | Glicoconjugados de precisão como ferramentas terapêuticas | |
WONG et al. | Sommaire du brevet 2959030 | |
WONG et al. | Patent 2959030 Summary | |
Lunghi | Immunotherapy of Tumours: Synthesis of a Mimetic of GM3 Ganglioside Antigen |